European Association of Urology Guidelines 2021

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EAU Guidelines on Management of Non-Neurogenic Male Lower Urinary Tract Symptoms (LUTS), incl. Benign Prostatic Obstruction (BPO) S. Gravas (Chair), J.N. Cornu, M. Gacci, C. Gratzke, T.R.W. Herrmann, C. Mamoulakis, M. Rieken, M.J. Speakman, K.A.O. Tikkinen Guidelines Associates: M. Karavitakis, I. Kyriazis, S. Malde, V. Sakalis, R. Umbach

© European Association of Urology 2021

TABLE OF CONTENTS

PAGE

1. INTRODUCTION 1.1 Aim and objectives 1.2 Panel composition 1.3 Available publications 1.4 Publication history

4 4 4 4 4

2.

METHODS 2.1 Introduction 2.2 Review 2.3 Patients to whom the guidelines apply

4 4 5 5

3.

EPIDEMIOLOGY, AETIOLOGY AND PATHOPHYSIOLOGY

5

4. DIAGNOSTIC EVALUATION 4.1 Medical history 4.2 Symptom score questionnaires 4.2.1 The International Prostate Symptom Score (IPSS) 4.2.2 The International Consultation on Incontinence Questionnaire (ICIQ-MLUTS) 4.2.3 Danish Prostate Symptom Score (DAN-PSS) 4.3 Frequency volume charts and bladder diaries 4.4 Physical examination and digital-rectal examination 4.4.1 Digital-rectal examination and prostate size evaluation 4.5 Urinalysis 4.6 Prostate-specific antigen (PSA) 4.6.1 PSA and the prediction of prostatic volume 4.6.2 PSA and the probability of PCa 4.6.3 PSA and the prediction of BPO-related outcomes 4.7 Renal function measurement 4.8 Post-void residual urine 4.9 Uroflowmetry 4.10 Imaging 4.10.1 Upper urinary tract 4.10.2 Prostate 4.10.2.1 Prostate size and shape 4.10.3 Voiding cysto-urethrogram 4.11 Urethrocystoscopy 4.12 Urodynamics 4.12.1 Diagnosing bladder outlet obstruction 4.12.2 Videourodynamics 4.13 Non-invasive tests in diagnosing bladder outlet obstruction in men with LUTS 4.13.1 Prostatic configuration/intravesical prostatic protrusion (IPP) 4.13.2 Bladder/detrusor wall thickness and ultrasound-estimated bladder weight 4.13.3 Non-invasive pressure-flow testing 4.13.4 The diagnostic performance of non-invasive tests in diagnosing bladder outlet obstruction in men with LUTS compared with pressure-flow studies

6 6 7 7 7 7 7 8 8 8 9 9 9 9 9 10 10 11 11 11 11 11 11 12 12 12 13 13 13 14 14

5. DISEASE MANAGEMENT 15 5.1 Conservative treatment 15 5.1.1 Watchful waiting (WW) 16 5.1.2 Behavioural and dietary modifications 16 5.1.3 Practical considerations 16 5.2 Pharmacological treatment 17 5.2.1 α1-Adrenoceptor antagonists (α1-blockers) 17 5.2.2 5α-reductase inhibitors 18 5.2.3 Muscarinic receptor antagonists 19 5.2.4 Beta-3 agonist 20 5.2.5 Phosphodiesterase 5 inhibitors 22 5.2.6 Plant extracts - phytotherapy 23

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5.2.7 Combination therapies 5.2.7.1 α1-blockers + 5α-reductase inhibitors 5.2.7.2 α1-blockers + muscarinic receptor antagonists 5.3 Surgical treatment 5.3.1 Resection of the prostate 5.3.1.1 Monopolar and bipolar transurethral resection of the prostate 5.3.1.2 Holmium laser resection of the prostate 5.3.1.3 Thulium:yttrium-aluminium-garnet laser (Tm:YAG) vaporesection of the prostate Mechanism of action: 5.3.1.4 Transurethral incision of the prostate 5.3.2 Enucleation of the prostate 5.3.2.1 Open prostatectomy 5.3.2.2 Bipolar transurethral enucleation of the prostate (B-TUEP) 5.3.2.3 Holmium laser enucleation of the prostate 5.3.2.4 Thulium:yttrium-aluminium-garnet laser (Tm:YAG) enucleation of the prostate Mechanism of action: 5.3.2.5 Diode laser enucleation of the prostate 5.3.2.6 Enucleation techniques under investigation 5.3.2.6.1 Minimal invasive simple prostatectomy 5.3.2.6.2 532 nm (‘Greenlight’) laser enucleation of the prostate 5.3.3 Vaporisation of the prostate 5.3.3.1 Bipolar transurethral vaporisation of the prostate 5.3.3.2 532 nm (‘Greenlight’) laser vaporisation of the prostate 5.3.3.3 Vaporisation techniques under investigation 5.3.3.3.1 Diode laser vaporisation of the prostate 5.3.4 Alternative ablative techniques 5.3.4.1 Aquablation – image guided robotic waterjet ablation: AquaBeam 5.3.4.2 Prostatic artery embolisation 5.3.4.3 Alternative ablative techniques under investigation 5.3.4.3.1 Convective water vapour energy (WAVE) ablation: The Rezum system 5.3.5 Alternative ablative techniques under investigation 5.3.5.1 Prostatic urethral lift 5.3.5.2 Intra-prostatic injections 5.3.5.3 Non-ablative techniques under investigation 5.3.5.3.1 (i)TIND 5.4 Patient selection 5.5 Management of Nocturia in men with lower urinary tract symptoms 5.5.1 Diagnostic assessment 5.5.2 Medical conditions and sleep disorders Shared Care Pathway 5.5.3 Treatment for Nocturia 5.5.3.1 Antidiuretic therapy 5.5.3.2 Medications to treat LUTD 5.5.3.3 Other medications

42 42 42 43 44 44 44 47 47 47 49 49 50 50

6.

FOLLOW-UP 6.1 Watchful waiting (behavioural) 6.2 Medical treatment 6.3 Surgical treatment

51 51 51 52

7.

REFERENCES

52

8.

CONFLICT OF INTEREST

81

9.

CITATION INFORMATION

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1.

INTRODUCTION

1.1

Aim and objectives

Lower urinary tract symptoms (LUTS) are a common complaint in adult men with a major impact on quality of life (QoL), and have a substantial economic burden. The present Guidelines offer practical evidence-based guidance on the assessment and treatment of men aged 40 years or older with various non-neurogenic benign forms of LUTS. The understanding of the LUT as a functional unit, and the multifactorial aetiology of associated symptoms, means that LUTS now constitute the main focus, rather than the former emphasis on Benign Prostatic Hyperplasia (BPH). The term BPH is now regarded as inappropriate as it is Benign Prostatic Obstruction (BPO) that is treated if the obstruction is a significant cause of a man’s LUTS. It must be emphasised that clinical guidelines present the best evidence available to the experts. However, following guideline recommendations will not necessarily result in the best outcome. Guidelines can never replace clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions - also taking personal values and preferences/individual circumstances of patients into account. Guidelines are not mandates and do not purport to be a legal standard of care.

1.2

Panel composition

The EAU Non-neurogenic Male LUTS Guidelines Panel consists of an international group of experts with urological and clinical epidemiological backgrounds. All experts involved in the production of this document have submitted potential conflict of interest statements which can be viewed on the EAU website Uroweb: http://uroweb.org/guideline/treatment-of-non-neurogenic-male-luts/.

1.3

Available publications

A quick reference document, the Pocket Guidelines, is available in print and as an app for iOS and Android devices. These are abridged versions which may require consultation together with the full text version. All documents are accessible through the EAU website Uroweb: http://www.uroweb.org/guideline/treatment-ofnon-neurogenic-male-luts/.

1.4

Publication history

The Non-neurogenic Male LUTS Guidelines was first published in 2000. The 2021 document presents a limited update of the 2020 publication; the next full update of the Non-neurogenic Male LUTS Guidelines will be presented in 2022.

2.

METHODS

2.1

Introduction

For the 2021 Management of Non-Neurogenic Male LUTS Guidelines, a detailed review and restructuring of section 5.3 Surgical Treatment has been undertaken. Section 5.3 has been restructured to reflect surgical approach rather than specific technologies and is now divided into five sections: resection; enucleation; vaporisation; alternative ablative techniques; and non-ablative techniques. The literature cut-off date for section 5.3 is April 2019. In addition, a broad and comprehensive literature search related to Serenoa repens in section 5.2.5 Plant extracts – phytotherapy was performed covering the timeframe between the search cut-off date of the EU monograph on S. repens [1] and April 2020. A detailed search strategy is available online: http://www. uroweb.org/guideline/treatment-of-non-neurogenic-male-luts/supplementary-material. For each recommendation within the guidelines there is an accompanying online strength rating form, the bases of which is a modified GRADE methodology [2, 3]. Each strength rating form addresses a number of key elements namely: 1. the overall quality of the evidence which exists for the recommendation, references used in this text are graded according to a classification system modified from the Oxford Centre for Evidence-Based Medicine Levels of Evidence [4]; 2. the magnitude of the effect (individual or combined effects); 3. the certainty of the results (precision, consistency, heterogeneity and other statistical or study related factors); 4. the balance between desirable and undesirable outcomes; 5. the impact of patient values and preferences on the intervention; 6. the certainty of those patient values and preferences.

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These key elements are the basis which panels use to define the strength rating of each recommendation. The strength of each recommendation is represented by the words ‘strong’ or ‘weak’ [5]. The strength of each recommendation is determined by the balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including certainty of estimates), and nature and variability of patient values and preferences. Additional information can be found in the general Methodology section of this print, and online at the EAU website; http://www.uroweb.org/guideline/. A list of associations endorsing the EAU Guidelines can also be viewed online at the above address.

2.2

Review

The Non-Neurogenic Male LUTS Guidelines were peer reviewed prior to publication in 2016.

2.3

Patients to whom the guidelines apply

Recommendations apply to men aged 40 years or older who seek professional help for LUTS in various nonneurogenic and non-malignant conditions such as BPO, detrusor overactivity/overactive bladder (OAB), or nocturnal polyuria. Men with other associated factors relevant to LUT disease (e.g. concomitant neurological diseases, young age, prior LUT disease or surgery) usually require a more extensive work-up, which is not covered in these Guidelines, but may include several tests mentioned in the following sections. EAU Guidelines on Neuro-Urology, Urinary Incontinence, Urological Infections, Urolithiasis, or malignant diseases of the LUT have been developed by other EAU Guidelines Panels and are available online: www.uroweb.org/guidelines/.

3.

EPIDEMIOLOGY, AETIOLOGY AND PATHOPHYSIOLOGY

Lower urinary tract symptoms can be divided into storage, voiding and post-micturition symptoms [6], they are prevalent, cause bother and impair QoL [7-10]. An increasing awareness of LUTS and storage symptoms in particular, is warranted to discuss management options that could increase QoL [11]. Lower urinary tract symptoms are strongly associated with ageing [7, 8], associated costs and burden are therefore likely to increase with future demographic changes [8, 12]. Lower urinary tract symptoms are also associated with a number of modifiable risk factors, suggesting potential targets for prevention (e.g. metabolic syndrome) [13]. In addition, men with moderate-to-severe LUTS may have an increased risk of major adverse cardiac events [14]. Most elderly men have at least one LUTS [8]; however, symptoms are often mild or not very bothersome [10, 11, 15]. Lower urinary tract symptoms can progress dynamically: for some individuals LUTS persist and progress over long time periods, and for others they remit [8]. Lower urinary tract symptoms have traditionally been related to bladder outlet obstruction (BOO), most frequently when histological BPH progresses through benign prostatic enlargement (BPE) to BPO [6, 9]. However, increasing numbers of studies have shown that LUTS are often unrelated to the prostate [8, 16]. Bladder dysfunction may also cause LUTS, including detrusor overactivity/OAB, detrusor underactivity/underactive bladder, as well as other structural or functional abnormalities of the urinary tract and its surrounding tissues [16]. Prostatic inflammation also appears to play a role in BPH pathogenesis and progression [17, 18]. In addition, many non-urological conditions also contribute to urinary symptoms, especially nocturia [8]. The definitions of the most common conditions related to male LUTS are presented below: • Acute retention of urine is defined as a painful, palpable or percussible bladder, when the patient is unable to pass any urine [6]. • Chronic retention of urine is defined as a non-painful bladder, which remains palpable or percussible after the patient has passed urine. Such patients may be incontinent [6]. • Bladder outlet obstruction is the generic term for obstruction during voiding and is characterised by increasing detrusor pressure and reduced urine flow rate. It is usually diagnosed by studying the synchronous values of flow-rate and detrusor pressure [6]. • Benign prostatic obstruction is a form of BOO and may be diagnosed when the cause of outlet obstruction is known to be BPE [6]. In the Guidelines the term BPO or BOO is used as reported by the original studies. • Benign prostatic hyperplasia is a term used (and reserved) for the typical histological pattern, which defines the disease.

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•

•

Detrusor overactivity (DO) is a urodynamic observation characterised by involuntary detrusor contractions during the filling phase which may be spontaneous or provoked [6]. Detrusor overactivity is usually associated with overactive bladder syndrome characterised by urinary urgency, with or without urgency urinary incontinence, usually with increased daytime frequency and nocturia, if there is no proven infection or other obvious pathology [19]. Detrusor underactivity (DU) during voiding is characterised by decreased detrusor voiding pressure leading to a reduced urine flow rate. Detrusor underactivity causes underactive bladder syndrome which is characterised by voiding symptoms similar to those caused by BPO [20].

Figure 1 illustrates the potential causes of LUTS. In any man complaining of LUTS, it is common for more than one of these factors to be present. Figure 1: Causes of male LUTS

Overacve bladder/ Detrusor overacvity

Benign prostac obstrucon

Others

Distal ureteric stone

Nocturnal polyuria

Underacve bladder/ Detrusor underacvity

Bladder tumour

LUTS

Chronic Pelvic Pain syndrome

Urethral stricture

Neurogenic bladder dysfuncon

4.

Urinary tract infecon / Inflammaon

Foreign body

DIAGNOSTIC EVALUATION

Tests are useful for diagnosis, monitoring, assessing the risk of disease progression, treatment planning, and the prediction of treatment outcomes. The clinical assessment of patients with LUTS has two main objectives: • to identify the differential diagnoses, since the origin of male LUTS is multifactorial, the relevant EAU Guidelines on the management of applicable conditions should be followed; • to define the clinical profile (including the risk of disease progression) of men with LUTS in order to provide appropriate care.

4.1

Medical history

The importance of assessing the patient’s history is well recognised [21-23]. A medical history aims to identify the potential causes and relevant comorbidities, including medical and neurological diseases. In addition,

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current medication, lifestyle habits, emotional and psychological factors must be reviewed. The Panel recognises the need to discuss LUTS and the therapeutic pathway from the patient’s perspective. This includes reassuring the patient that there is no definite link between LUTS and prostate cancer (PCa) [24, 25]. As part of the urological/surgical history, a self-completed validated symptom questionnaire (see section 4.2) should be obtained to objectify and quantify LUTS. Bladder diaries or frequency volume charts are particularly beneficial when assessing patients with nocturia and/or storage symptoms (see section 4.3). Sexual function should also be assessed, preferably with validated symptom questionnaires such as the International Index for Erectile Function (IIEF) [26]. Summary of evidence A medical history is an integral part of a patient’s medical evaluation. A medical history aims to identify the potential causes of LUTS as well as any relevant comorbidities and to review the patient’s current medication and lifestyle habits. Recommendation Take a complete medical history from men with LUTS.

4.2

LE 4 4

Strength rating Strong

Symptom score questionnaires

All published guidelines for male LUTS recommend using validated symptom score questionnaires [21, 23]. Several questionnaires have been developed which are sensitive to symptom changes and can be used to monitor treatment [27-33]. Symptom scores are helpful in quantifying LUTS and in identifying which type of symptoms are predominant; however, they are not disease-, gender-, or age-specific. A systematic review (SR) evaluating the diagnostic accuracy of individual symptoms and questionnaires, compared with urodynamic studies (the reference standard), for the diagnosis of BOO in males with LUTS found that individual symptoms and questionnaires for diagnosing BOO were not significantly associated with one another [34]. 4.2.1 The International Prostate Symptom Score (IPSS) The IPSS is an eight-item questionnaire, consisting of seven symptom questions and one QoL question [28]. The IPSS score is categorised as ‘asymptomatic’ (0 points), ‘mildly symptomatic’ (1-7 points), ‘moderately symptomatic’ (8-19 points), and ‘severely symptomatic’ (20-35 points). Limitations include lack of assessment of incontinence, post-micturition symptoms, and bother caused by each separate symptom. 4.2.2 The International Consultation on Incontinence Questionnaire (ICIQ-MLUTS) The ICIQ-MLUTS was created from the International Continence Society (ICS) Male questionnaire. It is a widely used and validated patient completed questionnaire including incontinence questions and bother for each symptom [29]. It contains thirteen items, with subscales for nocturia and OAB, and is available in seventeen languages. 4.2.3 Danish Prostate Symptom Score (DAN-PSS) The DAN-PSS [32] is a symptom score used mainly in Denmark and Finland. The DAN-PSS also has questions on incontinence and measures the bother of each individual LUTS. Summary of evidence LE Symptom questionnaires are sensitive to symptom changes. 3 Symptom scores can quantify LUTS and identify which types of symptoms are predominant; however, 3 they are not disease-, gender-, or age-specific. Recommendation Use a validated symptom score questionnaire including bother and quality of life assessment during the assessment of male LUTS and for re-evaluation during and/or after treatment.

4.3

Strength rating Strong

Frequency volume charts and bladder diaries

The recording of volume and time of each void by the patient is referred to as a frequency volume chart (FVC). Inclusion of additional information such as fluid intake, use of pads, activities during recording, or which grades of symptom severity and bladder sensation is termed a bladder diary [6]. Parameters that can be derived from the FVC and bladder diary include: day-time and night-time voiding frequency, total voided volume, the fraction of urine production during the night (nocturnal polyuria index), and volume of individual voids.

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The mean 24-hour urine production is subject to considerable variation. Likewise, circumstantial influence and intra-individual variation cause FVC parameters to fluctuate, though there is comparatively little data [35, 36]. The FVC/bladder diary is particularly relevant in nocturia, where it underpins the categorisation of underlying mechanism(s) [37-39]. The use of FVCs may cause a ‘bladder training effect’ and influence the frequency of nocturnal voids [40]. The duration of the FVC/bladder diary needs to be long enough to avoid sampling errors, but short enough to avoid non-compliance [41]. A SR of the available literature recommended FVCs should continue for three or more days [42]. The ICIQ-Bladder diary (ICIQ-BD) is the only diary that has undergone full validation [43]. Summary of evidence Frequency volume charts and bladder diaries provide real-time documentation of urinary function and reduce recall bias. Three and seven day FVCs provide reliable measurement of urinary symptoms in patients with LUTS.

LE 3 2b

Recommendations Strength rating Use a bladder diary to assess male LUTS with a prominent storage component or nocturia. Strong Tell the patient to complete a bladder diary for at least three days.

4.4

Strong

Physical examination and digital-rectal examination

Physical examination particularly focusing on the suprapubic area, the external genitalia, the perineum and lower limbs should be performed. Urethral discharge, meatal stenosis, phimosis and penile cancer must be excluded. 4.4.1 Digital-rectal examination and prostate size evaluation Digital-rectal examination (DRE) is the simplest way to assess prostate volume, but the correlation to prostate volume is poor. Quality-control procedures for DRE have been described [44]. Transrectal ultrasound (TRUS) is more accurate in determining prostate volume than DRE. Underestimation of prostate volume by DRE increases with increasing TRUS volume, particularly where the volume is > 30 mL [45]. A model of visual aids has been developed to help urologists estimate prostate volume more accurately [46]. One study concluded that DRE was sufficient to discriminate between prostate volumes > or < 50 mL [47]. Summary of evidence Physical examination is an integral part of a patient’s medical evaluation. Digital-rectal examination can be used to assess prostate volume; however, the correlation to actual prostate volume is poor. Recommendation Perform a physical examination including digital rectal examination in the assessment of male LUTS.

4.5

LE 4 3

Strength rating Strong

Urinalysis

Urinalysis (dipstick or sediment) must be included in the primary evaluation of any patient presenting with LUTS to identify conditions, such as urinary tract infections (UTI), microhaematuria and diabetes mellitus. If abnormal findings are detected further tests are recommended according to other EAU Guidelines, e.g. Guidelines on urinary tract cancers and urological infections [48-51]. Urinalysis is recommended in most Guidelines in the primary management of patients with LUTS [52, 53]. There is limited evidence, but general expert consensus suggests that the benefits outweigh the costs [54]. The value of urinary dipstick/microscopy for diagnosing UTI in men with LUTS without acute frequency and dysuria has been questioned [55]. Summary of evidence Urinalysis (dipstick or sediment) may indicate a UTI, proteinuria, haematuria or glycosuria requiring further assessment. The benefits of urinalysis outweigh the costs.

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LE 3 4

MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021

Recommendation Use urinalysis (by dipstick or urinary sediment) in the assessment of male LUTS.

4.6

Strength rating Strong

Prostate-specific antigen (PSA)

4.6.1 PSA and the prediction of prostatic volume Pooled analysis of placebo-controlled trials of men with LUTS and presumed BPO showed that PSA has a good predictive value for assessing prostate volume, with areas under the curve (AUC) of 0.76-0.78 for various prostate volume thresholds (30 mL, 40 mL, and 50 mL). To achieve a specificity of 70%, whilst maintaining a sensitivity between 65-70%, approximate age-specific criteria for detecting men with prostate glands exceeding 40 mL are PSA > 1.6 ng/mL, > 2.0 ng/mL, and > 2.3 ng/mL, for men with BPH in their 50s, 60s, and 70s, respectively [56]. A strong association between PSA and prostate volume was found in a large community-based study in the Netherlands [57]. A PSA threshold value of 1.5 ng/mL could best predict a prostate volume of > 30 mL, with a positive predictive value (PPV) of 78%. The prediction of prostate volume can also be based on total and free PSA. Both PSA forms predict the TRUS prostate volume (± 20%) in > 90% of the cases [58, 59]. 4.6.2 PSA and the probability of PCa The role of PSA in the diagnosis of PCa is presented by the EAU Guidelines on Prostate Cancer [60]. The potential benefits and harms of using serum PSA testing to diagnose PCa in men with LUTS should be discussed with the patient. 4.6.3 PSA and the prediction of BPO-related outcomes Serum PSA is a stronger predictor of prostate growth than prostate volume [61]. In addition, the PLESS study showed that PSA also predicted the changes in symptoms, QoL/bother, and maximum flow-rate (Qmax) [62]. In a longitudinal study of men managed conservatively, PSA was a highly significant predictor of clinical progression [63, 64]. In the placebo arms of large double-blind studies, baseline serum PSA predicted the risk of acute urinary retention (AUR) and BPO-related surgery [65, 66]. An equivalent link was also confirmed by the Olmsted County Study. The risk for treatment was higher in men with a baseline PSA of > 1.4 ng/mL [67]. Patients with BPO seem to have a higher PSA level and larger prostate volumes. The PPV of PSA for the detection of BPO was recently shown to be 68% [68]. Furthermore, in an epidemiological study, elevated free PSA levels could predict clinical BPH, independent of total PSA levels [69]. Summary of evidence Prostate-specific antigen has a good predictive value for assessing prostate volume and is a strong predictor of prostate growth. Baseline PSA can predict the risk of AUR and BPO-related surgery. Recommendations Measure prostate-specific antigen (PSA) if a diagnosis of prostate cancer will change management. Measure PSA if it assists in the treatment and/or decision making process.

4.7

LE 1b 1b

Strength rating Strong Strong

Renal function measurement

Renal function may be assessed by serum creatinine or estimated glomerular filtration rate (eGFR). Hydronephrosis, renal insufficiency or urinary retention are more prevalent in patients with signs or symptoms of BPO [70]. Even though BPO may be responsible for these complications, there is no conclusive evidence on the mechanism [71]. One study reported that 11% of men with LUTS had renal insufficiency [70]. Neither symptom score nor QoL was associated with the serum creatinine level. Diabetes mellitus or hypertension were the most likely causes of the elevated creatinine concentration. Comiter et al. [72] reported that non-neurogenic voiding dysfunction is not a risk factor for elevated creatinine levels. Koch et al. [73] concluded that only those with an elevated creatinine level require investigational ultrasound (US) of the kidney. In the Olmsted County Study community-dwelling men there was a cross-sectional association between signs and symptoms of BPO (though not prostate volume) and chronic kidney disease (CKD) [74]. In 2,741 consecutive patients who presented with LUTS, decreased Qmax, a history of hypertension and/or diabetes were associated with CKD [75]. Another study demonstrated a correlation between Qmax and eGFR in middle-aged men with moderate-to-severe LUTS [76]. Patients with renal insufficiency are at an increased risk of developing post-operative complications [77].

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Summary of evidence Decreased Qmax and a history of hypertension and/or diabetes are associated with CKD in patients who present with LUTS. Patients with renal insufficiency are at an increased risk of developing post-operative complications. Recommendation Assess renal function if renal impairment is suspected based on history and clinical examination, or in the presence of hydronephrosis, or when considering surgical treatment for male LUTS.

4.8

LE 3 3

Strength rating Strong

Post-void residual urine

Post-void residual (PVR) urine can be assessed by transabdominal US, bladder scan or catheterisation. Post-void residual is not necessarily associated with BOO, since high PVR volumes can be a consequence of obstruction and/or poor detrusor function (DU) [78, 79]. Using a PVR threshold of 50 mL, the diagnostic accuracy of PVR measurement has a PPV of 63% and a negative predictive value (NPV) of 52% for the prediction of BOO [80]. A large PVR is not a contraindication to watchful waiting (WW) or medical therapy, although it may indicate a poor response to treatment and especially to WW. In both the MTOPS and ALTESS studies, a high baseline PVR was associated with an increased risk of symptom progression [65, 66]. Monitoring of changes in PVR over time may allow for identification of patients at risk of AUR [81]. This is of particular importance for the treatment of patients using antimuscarinic medication. In contrast, baseline PVR has little prognostic value for the risk of BPO-related invasive therapy in patients on α1-blockers or WW [82]. However, due to large test-retest variability and lack of outcome studies, no PVR threshold for treatment decision has yet been established; this is a research priority. Summary of evidence The diagnostic accuracy of PVR measurement, using a PVR threshold of 50 mL, has a PPV of 63% and a NPV of 52% for the prediction of BOO. Monitoring of changes in PVR over time may allow for identification of patients at risk of AUR. Recommendation Measure post-void residual in the assessment of male LUTS.

4.9

LE 3 3

Strength rating Weak

Uroflowmetry

Urinary flow rate assessment is a widely used non-invasive urodynamic test. Key parameters are Qmax and flow pattern. Uroflowmetry parameters should preferably be evaluated with voided volume > 150 mL. As Qmax is prone to within-subject variation [83, 84], it is useful to repeat uroflowmetry measurements, especially if the voided volume is < 150 mL, or Qmax or flow pattern is abnormal. The diagnostic accuracy of uroflowmetry for detecting BOO varies considerably and is substantially influenced by threshold values. A threshold Qmax of 10 mL/s has a specificity of 70%, a PPV of 70% and a sensitivity of 47% for BOO. The specificity using a threshold Qmax of 15 mL/s was 38%, the PPV 67% and the sensitivity 82% [85]. If Qmax is > 15 mL/s, physiological compensatory processes mean that BOO cannot be excluded. Low Qmax can arise as a consequence of BOO [86], DUA or an under-filled bladder [87]. Therefore, it is limited as a diagnostic test as it is unable to discriminate between the underlying mechanisms. Specificity can be improved by repeated flow rate testing. Uroflowmetry can be used for monitoring treatment outcomes [88] and correlating symptoms with objective findings. Summary of evidence The diagnostic accuracy of uroflowmetry for detecting BOO varies considerably and is substantially influenced by threshold values. Specificity can be improved by repeated flow rate testing.

LE 2b

Recommendations Perform uroflowmetry in the initial assessment of male LUTS.

Strength rating Weak

Perform uroflowmetry prior to medical or invasive treatment.

Strong

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4.10

Imaging

4.10.1 Upper urinary tract Men with LUTS are not at increased risk for upper tract malignancy or other abnormalities when compared to the overall population [73, 89-91]. Several arguments support the use of renal US in preference to intravenous urography. Ultrasound allows for better characterisation of renal masses, the possibility of investigating the liver and retroperitoneum, and simultaneous evaluation of the bladder, PVR and prostate, together with a lower cost, radiation dose and less side effects [89]. Ultrasound can be used for the evaluation of men with large PVR, haematuria, or a history of urolithiasis. Summary of evidence Men with LUTS are not at increased risk for upper tract malignancy or other abnormalities when compared to the overall population. Ultrasound can be used for the evaluation of men with large PVR, haematuria, or a history of urolithiasis. Recommendation Perform ultrasound of the upper urinary tract in men with LUTS.

LE 3 4

Strength rating Weak

4.10.2 Prostate Imaging of the prostate can be performed by transabdominal US, TRUS, computed tomography (CT), and magnetic resonance imaging (MRI). However, in daily practice, prostate imaging is performed by transabdominal (suprapubic) US or TRUS [89]. 4.10.2.1 Prostate size and shape Assessment of prostate size is important for the selection of interventional treatment, i.e. open prostatectomy (OP), enucleation techniques, transurethral resection, transurethral incision of the prostate (TUIP), or minimally invasive therapies. It is also important prior to treatment with 5α-reductase inhibitors (5-ARIs). Prostate volume predicts symptom progression and the risk of complications [91]. Transrectal US is superior to transabdominal volume measurement [92, 93]. The presence of a median lobe may guide treatment choice in patients scheduled for a minimally invasive approach since medial lobe presence can be a contraindication for some minimally invasive treatments (see section 5.3). Summary of evidence Assessment of prostate size by TRUS or transabdominal US is important for the selection of interventional treatment and prior to treatment with 5-ARIs. Recommendations Perform imaging of the prostate when considering medical treatment for male LUTS, if it assists in the choice of the appropriate drug. Perform imaging of the prostate when considering surgical treatment.

LE 3

Strength rating Weak Strong

4.10.3 Voiding cysto-urethrogram Voiding cysto-urethrogram (VCUG) is not recommended in the routine diagnostic work-up of men with LUTS, but it may be useful for the detection of vesico-ureteral reflux, bladder diverticula, or urethral pathologies. Retrograde urethrography may additionally be useful for the evaluation of suspected urethral strictures.

4.11

Urethrocystoscopy

Patients with a history of microscopic or gross haematuria, urethral stricture, or bladder cancer, who present with LUTS, should undergo urethrocystoscopy during diagnostic evaluation. The evaluation of a prostatic middle lobe with urethrocystocopy should be performed when considering interventional treatments for which the presence of middle lobe is a contraindication. A prospective study evaluated 122 patients with LUTS using uroflowmetry and urethrocystoscopy [94]. The pre-operative Qmax was normal in 25% of 60 patients who had no bladder trabeculation, 21% of 73 patients with mild trabeculation and 12% of 40 patients with marked trabeculation on cystoscopy. All 21 patients who presented with diverticula had a reduced Qmax. Another study showed that there was no significant correlation between the degree of bladder trabeculation (graded from I to IV), and the pre-operative Qmax value in 39 symptomatic men aged 53-83 years [95]. The largest study published on this issue examined the relation of urethroscopic findings to urodynamic

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studies in 492 elderly men with LUTS [96]. The authors noted a correlation between cystoscopic appearance (grade of bladder trabeculation and urethral occlusion) and urodynamic indices, DO and low compliance. It should be noted, however, that BOO was present in 15% of patients with normal cystoscopic findings, while 8% of patients had no obstruction, even in the presence of severe trabeculation [96]. Summary of evidence Patients with a history of microscopic or gross haematuria, urethral stricture, or bladder cancer, who present with LUTS, should undergo urethrocystoscopy during diagnostic evaluation. None of the studies identified a strong association between the urethrocystoscopic and urodynamic findings. Recommendation Perform urethrocystoscopy in men with LUTS prior to minimally invasive/surgical therapies if the findings may change treatment.

4.12

LE 3 3

Strength rating Weak

Urodynamics

In male LUTS, the most widespread invasive urodynamic techniques employed are filling cystometry and pressure flow studies (PFS). The major goal of urodynamics is to explore the functional mechanisms of LUTS, to identify risk factors for adverse outcomes and to provide information for shared decision-making. Most terms and conditions (e.g. DO, low compliance, BOO/BPO, DUA) are defined by urodynamic investigation. 4.12.1 Diagnosing bladder outlet obstruction Pressure flow studies (PFS) are used to diagnose and define the severity of BOO, which is characterised by increased detrusor pressure and decreased urinary flow rate during voiding. Bladder outlet obstruction/BPO has to be differentiated from DUA, which exhibits decreased detrusor pressure during voiding in combination with decreased urinary flow rate [6]. Urodynamic testing may also identify DO. Studies have described an association between BOO and DO [97, 98]. In men with LUTS attributed to BPO, DO was present in 61% and independently associated with BOO grade and ageing [97]. The prevalence of DUA in men with LUTS is 11-40% [99, 100]. Detrusor contractility does not appear to decline in long-term BOO and surgical relief of BOO does not improve contractility [101, 102]. There are no published RCTs in men with LUTS and possible BPO that compare the standard practice investigation (uroflowmetry and PVR measurement) with PFS with respect to the outcome of treatment; however, a study has been completed in the UK, but the final results have not yet been published [103, 104]. Once available they will be included in the next edition of the Guidelines. A Cochrane meta-analysis was done to determine whether performing invasive urodynamic investigation reduces the number of men with continuing symptoms of voiding dysfunction. Two trials with 350 patients were included. Invasive urodynamic testing changed clinical decision making. Patients who underwent urodynamics were less likely to undergo surgery; however, no evidence was found to demonstrate whether this led to reduced symptoms of voiding dysfunction after treatment [105]. A more recent meta-analysis of retrospective studies showed that pre-operative urodynamic DOA has no diagnostic role in the prediction of surgical outcomes in patients with male BOO [106]. Due to the invasive nature of the test, a urodynamic investigation is generally only offered if conservative treatment has failed. The Guidelines Panel attempted to identify specific indications for PFS based on age, findings from other diagnostic tests and previous treatments. The Panel allocated a different degree of obligation for PFS in men > 80 years and men < 50 years, which reflects the lack of evidence. In addition, there was no consensus whether PFS should or may be performed when considering surgery in men with bothersome predominantly voiding LUTS and Qmax > 10 mL/s, although the Panel recognised that with a Qmax < 10 mL/s, BOO is likely and PFS is not necessarily needed. Patients with neurological disease, including those with previous radical pelvic surgery, should be assessed according to the EAU Guidelines on Neuro-Urology [107]. 4.12.2 Videourodynamics Videourodynamics provides additional anatomical and functional information and may be recommended if the clinician considers this is needed to understand the pathophysiological mechanism of an individual patient’s LUTS.

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Summary of evidence Within the literature cut-off dates of the 2021 edition of the Guidelines there were no RCTs in men with LUTS and possible BPO that compare the standard practice investigation (uroflowmetry and PVR measurement) with PFS with respect to the outcome of treatment. All subsequent RCTs will be evaluated for inclusion in the next edition of the Guidelines. Recommendations

LE 3

Strength rating

Perform pressure-flow studies (PFS) only in individual patients for specific indications prior Weak to invasive treatment or when further evaluation of the underlying pathophysiology of LUTS is warranted. Perform PFS in men who have had previous unsuccessful (invasive) treatment for LUTS. Weak Perform PFS in men considering invasive treatment who cannot void > 150 mL.

Weak

Perform PFS when considering surgery in men with bothersome predominantly voiding LUTS and Qmax > 10 mL/s. Perform PFS when considering invasive therapy in men with bothersome, predominantly voiding LUTS with a post void residual > 300 mL. Perform PFS when considering invasive treatment in men with bothersome, predominantly voiding LUTS aged > 80 years. Perform PFS when considering invasive treatment in men with bothersome, predominantly voiding LUTS aged < 50 years.

Weak

4.13

Weak Weak Weak

Non-invasive tests in diagnosing bladder outlet obstruction in men with LUTS

4.13.1 Prostatic configuration/intravesical prostatic protrusion (IPP) Prostatic configuration can be evaluated with TRUS, using the concept of the presumed circle area ratio (PCAR) [108]. The PCAR evaluates how closely the transverse US image of the prostate approaches a circular shape. The ratio tends toward one as the prostate becomes more circular. The sensitivity of PCAR was 77% for diagnosing BPO when PCAR was > 0.8, with 75% specificity [108]. Ultrasound measurement of IPP assesses the distance between the tip of the prostate median lobe and bladder neck in the midsagittal plane, using a suprapubically positioned US scanner, with a bladder volume of 150-250 mL; grade I protrusion is 0-4.9 mm, grade II is 5-10 mm and grade III is > 10 mm. Intravesical prostatic protrusion correlates well with BPO (presence and severity) on urodynamic testing, with a PPV of 94% and a NPV of 79% [109]. Intravesical prostatic protrusion may also correlate with prostate volume, DO, bladder compliance, detrusor pressure at maximum urinary flow, BOO index and PVR, and negatively correlates with Qmax [110]. Furthermore, IPP also appears to successfully predict the outcome of a trial without catheter after AUR [111, 112]. However, no information with regard to intra- or inter-observer variability and learning curve is yet available. Therefore, whilst IPP may be a feasible option to infer BPO in men with LUTS, the role of IPP as a non-invasive alternative to PFS in the assessment of male LUTS remains under evaluation. 4.13.2 Bladder/detrusor wall thickness and ultrasound-estimated bladder weight For bladder wall thickness (BWT) assessment, the distance between the mucosa and the adventitia is measured. For detrusor wall thickness (DWT) assessment, the only measurement needed is the detrusor sandwiched between the mucosa and adventitia [113]. A correlation between BWT and PFS parameters has been reported. A threshold value of 5 mm at the anterior bladder wall with a bladder filling of 150 mL was best at differentiating between patients with or without BOO [114]. Detrusor wall thickness at the anterior bladder wall with a bladder filling > 250 mL (threshold value for BOO > 2 mm) has a PPV of 94% and a specificity of 95%, achieving 89% agreement with PFS [73]. Threshold values of 2.0, 2.5, or 2.9 mm for DWT in patients with LUTS are able to identify 81%, 89%, and 100% of patients with BOO, respectively [115]. All studies found that BWT or DWT measurements have a higher diagnostic accuracy for detecting BOO than Qmax or Qave of free uroflowmetry, measurements of PVR, prostate volume, or symptom severity. One study could not demonstrate any difference in BWT between patients with normal urodynamics, BOO or DO. However, the study did not use a specific bladder filling volume for measuring BWT [116]. Disadvantages of the method include the lack of standardisation, and lack of evidence to indicate which measurement (BWT/DWT) is preferable [117]. Measurement of BWT/DWT is therefore not recommended for the diagnostic work-up of men with LUTS. Ultrasound-estimated bladder weight (UEBW) may identify BOO with a diagnostic accuracy of 86% at a cut-off value of 35 g [118, 119]. Severe LUTS and a high UEBW (> 35 g) are risk factors for prostate/BPH surgery in men on α-blockers [120].

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4.13.3 Non-invasive pressure-flow testing The penile cuff method, in which flow is interrupted to estimate isovolumetric bladder pressure, shows promising data, with good test repeatability [121] and interobserver agreement [122]. A nomogram has also been derived [123] whilst a method in which flow is not interrupted is also under investigation [124]. The data generated with the external condom method [125] correlates with invasive PFS in a high proportion of patients [126]. Resistive index [127] and prostatic urethral angle [128] have also been proposed, but are still experimental. The diagnostic performance of non-invasive tests in diagnosing bladder outlet obstruction in men with LUTS compared with pressure-flow studies The diagnostic performance of non-invasive tests in diagnosing BOO in men with LUTS compared with PFS has been investigated in a SR [129]. A total of 42 studies were included is this review. The majority were prospective cohort studies, and the diagnostic accuracy of the following non-invasive tests were assessed: penile cuff test; uroflowmetry; detrusor/bladder wall thickness; bladder weight; external condom catheter method; IPP; Doppler US; prostate volume/height; and near-infrared spectroscopy. Overall, although the majority of studies have a low risk of bias, data regarding the diagnostic accuracy of these non-invasive tests is limited by the heterogeneity of the studies in terms of the threshold values used to define BOO, the different urodynamic definitions of BOO used across different studies and the small number of studies for each test. It was found that specificity, sensitivity, PPV and NPV of the non-invasive tests were highly variable. Therefore, even though several tests have shown promising results regarding non-invasive diagnosis of BOO, invasive urodynamics remains the modality of choice. 4.13.4

Summary of evidence Data regarding the diagnostic accuracy of non-invasive tests is limited by the heterogeneity of the studies as well as the small number of studies for each test. Specificity, sensitivity, PPV and NPV of the non-invasive tests were highly variable. Recommendation Do not offer non-invasive tests as an alternative to pressure-flow studies for diagnosing bladder outlet obstruction in men.

14

LE 1a 1a

Strength rating Strong

MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021

Figure 2: Assessment algorithm of LUTS in men aged 40 years or older Readers are strongly recommended to read the full text that highlights the current position of each test in detail.

Male LUTS

History (+ sexual function) Symptom score questionnaire Urinalysis Physical examination PSA (if diagnosis of PCa will change the management – discuss with patient) Measurement of PVR

Abnormal DRE Suspicion of neurological disease High PSA Abnormal urinalysis

Evaluate according to relevant guidelines or clinical standard

Treat underlying condition (if any, otherwise return to initial assessment)

Manage according to EAU mLUTS treatment algorithm

No

Bothersome symptoms

Yes Significant PVR

US of kidneys +/- Renal function assessment

FVC in cases of predominant storage LUTS/nocturia US assessment of prostate Uroflowmetry

Medical treatment according to treatment algorithm

Benign conditions of bladder and/or prostate with baseline values PLAN TREATMENT

Endoscopy (if test would alter the choice of surgical modality) Pressure flow studies (see text for specific indications)

Surgical treatment according to treatment algorithm DRE = digital-rectal examination; FVC = frequency volume chart; LUTS = lower urinary tract symptoms; PCa = prostate cancer; PSA = prostate specific antigen; PVR = post-void residual; US = ultrasound.

5.

DISEASE MANAGEMENT

5.1

Conservative treatment

5.1.1 Watchful waiting (WW) Many men with LUTS are not troubled enough by their symptoms to need drug treatment or surgical intervention. All men with LUTS should be formally assessed prior to any allocation of treatment in order to establish symptom severity and to differentiate between men with uncomplicated (the majority) and

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complicated LUTS. Watchful waiting is a viable option for many men with non-bothersome LUTS as few will progress to AUR and complications (e.g. renal insufficiency or stones) [130, 131], whilst others can remain stable for years [132]. In one study, approximately 85% of men with mild LUTS were stable on WW at one year [133]. A study comparing WW and transurethral resection of the prostate (TURP) in men with moderate LUTS showed the surgical group had improved bladder function (flow rates and PVR volumes), especially in those with high levels of bother; 36% of WW patients crossed over to surgery within five years, leaving 64% doing well in the WW group [134, 135]. Increasing symptom bother and PVR volumes are the strongest predictors of WW failure. Men with mild-to-moderate uncomplicated LUTS who are not too troubled by their symptoms are suitable for WW. 5.1.2 Behavioural and dietary modifications It is customary for this type of management to include the following components: • education (about the patient’s condition); • reassurance (that cancer is not a cause of the urinary symptoms); • periodic monitoring; • lifestyle advice [132, 133, 136, 137] such as:: oo reduction of fluid intake at specific times aimed at reducing urinary frequency when most inconvenient (e.g. at night or when going out in public); oo avoidance/moderation of intake of caffeine or alcohol, which may have a diuretic and irritant effect, thereby increasing fluid output and enhancing frequency, urgency and nocturia; oo use of relaxed and double-voiding techniques; oo urethral milking to prevent post-micturition dribble; oo distraction techniques such as penile squeeze, breathing exercises, perineal pressure, and mental tricks to take the mind off the bladder and toilet, to help control OAB symptoms; oo bladder retraining that encourages men to hold on when they have urgency to increase their bladder capacity and the time between voids; oo reviewing the medication and optimising the time of administration or substituting drugs for others that have fewer urinary effects (these recommendations apply especially to diuretics); oo providing necessary assistance when there is impairment of dexterity, mobility, or mental state; oo treatment of constipation. There now exists evidence that self-management as part of WW reduces both symptoms and progression [136, 137]. Men randomised to three self-care management sessions in addition to standard care had better symptom improvement and QoL than men treated with standard care only, for up to a year [136]. 5.1.3 Practical considerations The components of self-care management have not been individually studied. The above components of lifestyle advice have been derived from formal consensus methodology [138]. Further research in this area is required. Summary of evidence Watchful waiting is usually a safe alternative for men who are less bothered by urinary difficulty or who wish to delay treatment. The treatment failure rate over a period of five years was 21%; 79% of patients were clinically stable. An additional study reported 81% of patients were clinically stable on WW after a mean follow-up of seventeen months. Men randomised to three self-management sessions in addition to standard care had better symptom improvement and QoL than men treated with standard care alone at up to a year. Self-care management as part of WW reduces both symptoms and progression. Recommendations Offer men with mild/moderate symptoms, minimally bothered by their symptoms, watchful waiting. Offer men with LUTS lifestyle advice and self-care information prior to, or concurrent with, treatment.

16

LE 1b

2 1b

Strength rating Strong Strong

MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021

5.2

Pharmacological treatment

5.2.1 α1-Adrenoceptor antagonists (α1-blockers) Mechanism of action: α1-blockers aim to inhibit the effect of endogenously released noradrenaline on smooth muscle cells in the prostate and thereby reduce prostate tone and BOO [139]. However, α1-blockers have little effect on urodynamically determined bladder outlet resistance [140], and treatment-associated improvement of LUTS correlates poorly with obstruction [141]. Thus, other mechanisms of action may also be relevant. Alpha 1-adrenoceptors located outside the prostate (e.g. urinary bladder and/or spinal cord) and α1-adrenoceptor subtypes (α1B- or α1D-adrenoceptors) may play a role as mediators of effects. Alpha 1-adrenoceptors in blood vessels, other non-prostatic smooth muscle cells, and the central nervous system may mediate adverse events. Currently available α1-blockers are: alfuzosin hydrochloride (alfuzosin); doxazosin mesylate (doxazosin); silodosin; tamsulosin hydrochloride (tamsulosin); terazosin hydrochloride (terazosin); and naftopidil. Alpha 1-blockers exist in different formulations. Although different formulations result in different pharmacokinetic and tolerability profiles, the overall difference in clinical efficacy between the difference formulations seems modest. Efficacy: Indirect comparisons and limited direct comparisons between α1-blockers demonstrate that all α1-blockers have a similar efficacy in appropriate doses [142]. Clinical effects take a few weeks to develop fully, but significant efficacy over placebo can occur within hours to days [141]. Controlled studies show that α1-blockers typically reduce IPSS by approximately 30-40% and increase Qmax by approximately 20-25%. However, considerable improvements also occurred in the corresponding placebo arms [63, 143]. In open-label studies, an IPSS improvement of up to 50% and Qmax increase of up to 40% were documented [63, 143]. A recent SR and meta-analysis suggested that Qmax variation underestimates the real effect of α1-blockers on BPO, as small improvements in Qmax correspond to relevant improvements in BOO index in PFS [144]. Alpha 1-blockers can reduce both storage and voiding LUTS. Prostate size does not affect α1-blocker efficacy in studies with follow-up periods of less than one year, but α1-blockers do seem to be more efficacious in patients with smaller prostates (< 40 mL) in longer-term studies [65, 145-148]. The efficacy of α1-blockers is similar across age groups [143]. In addition, α1-blockers neither reduce prostate size nor prevent AUR in long-term studies [146-148]; however, recent evidence suggests that the use of α1-blockers (alfuzosin and tamsulosin) may improve resolution of AUR [149]. Nonetheless, IPSS reduction and Qmax improvement during α1-blocker treatment appears to be maintained over at least four years. Tolerability and safety: Tissue distribution, subtype selectivity, and pharmacokinetic profiles of certain formulations may contribute to the tolerability profile of specific drugs. The most frequent adverse events of α1-blockers are asthenia, dizziness and (orthostatic) hypotension. Vasodilating effects are most pronounced with doxazosin and terazosin, and are less common with alfuzosin and tamsulosin [150]. Patients with cardiovascular comorbidity and/or vaso-active co-medication may be susceptible to α1-blocker-induced vasodilatation [151]. In contrast, the frequency of hypotension with the α1A-selective blocker silodosin is comparable with placebo [152]. In a large retrospective cohort analysis of men aged > 66 years treated with α1-blockers the risks of falling (odds ratio [OR] 1.14) and of sustaining a fracture (OR 1.16) was increased, most likely as a result of induced hypotension [153]. An adverse ocular event termed intra-operative floppy iris syndrome (IFIS) was reported in 2005, affecting cataract surgery [154]. A meta-analysis on IFIS after alfuzosin, doxazosin, tamsulosin or terazosin exposure showed an increased risk for all α1-blockers [155]. However, the OR for IFIS was much higher for tamsulosin. It appears prudent not to initiate α1-blocker treatment prior to scheduled cataract surgery, and the ophthalmologist should be informed about α1-blocker use. A SR concluded that α1-blockers do not adversely affect libido, have a small beneficial effect on erectile function, but can cause abnormal ejaculation [156]. Originally, abnormal ejaculation was thought to be retrograde, but more recent data demonstrate that it is due to a decrease or absence of seminal fluid during ejaculation, with young age being an apparent risk factor. In a recent meta-analysis ejaculatory dysfunction (EjD) was significantly more common with α1-blockers than with placebo (OR 5.88). In particular, EjD was significantly more commonly related with tamsulosin or silodosin (OR 8.57 and 32.5) than placebo, while both doxazosin and terazosin (OR 0.80 and 1.78) were associated with a low risk of EjD [157]. In the metaregression, the occurrence of EjD was independently associated with the improvement of urinary symptoms and flow rate, suggesting that the more effective the α1-blocker is the greater the incidence of EjD.

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Practical considerations: α1-blockers are usually considered the first-line drug treatment for male LUTS because of their rapid onset of action, good efficacy, and low rate and severity of adverse events. However, α1-blockers do not prevent occurrence of urinary retention or need for surgery. Ophthalmologists should be informed about α1-blocker use prior to cataract surgery. Elderly patients treated with non-selective α1-blockers should be informed about the risk of orthostatic hypotension. Sexually active patients treated with selective α1-blockers should be counselled about the risk of EjD. Summary of evidence α1-blockers are effective in reducing urinary symptoms (IPSS) and increasing the peak urinary flow rate (Qmax) compared with placebo. Alfuzosin, terazosin and doxazosin showed a statistically significant increased risk of developing vascular-related events compared with placebo. Alfuzosin, doxazosin, tamsulosin or terazosin exposure has been associated with an increased risk of IFIS. Ejaculatory dysfunction is significantly more common with α1-blockers than with placebo, particularly with more selective α1-blockers such as tamsulosin and silodosin. Recommendation Offer α1-blockers to men with moderate-to-severe LUTS.

LE 1a 1a 1a 1a

Strength rating Strong

5.2.2 5α-reductase inhibitors Mechanism of action: Androgen effects on the prostate are mediated by dihydrotestosterone (DHT), which is converted from testosterone by the enzyme 5α-reductase [158], which has two isoforms: • 5α-reductase type 1: predominant expression and activity in the skin and liver. • 5α-reductase type 2: predominant expression and activity in the prostate. Two 5-ARIs are available for clinical use: dutasteride and finasteride. Finasteride inhibits only 5α-reductase type 2, whereas dutasteride inhibits both 5α-reductase types (dual 5-ARI). The 5-ARIs induce apoptosis of prostate epithelial cells [159] leading to prostate size reduction of about 18-28% and a decrease in circulating PSA levels of about 50% after six to twelve months of treatment [160]. Mean prostate volume and PSA reduction may be even more pronounced after long-term treatment. Continuous treatment reduces the serum DHT concentration by approximately 70% with finasteride and 95% with dutasteride. However, prostate DHT concentration is reduced to a similar level (85-90%) by both 5-ARIs. Efficacy: Clinical effects relative to placebo are seen after treatment of at least six months. After two to four years of treatment 5-ARIs improve IPSS by approximately 15-30%, decrease prostate volume by 18-28%, and increase Qmax by 1.5-2.0 mL/s in patients with LUTS due to prostate enlargement [65, 147, 148, 161-167]. An indirect comparison and one direct comparative trial (twelve months duration) indicate that dutasteride and finasteride are equally effective in the treatment of LUTS [160, 168]. Symptom reduction depends on initial prostate size. Finasteride may not be more efficacious than placebo in patients with prostates < 40 mL [169]. However, dutasteride seems to reduce IPSS, prostate volume, and the risk of AUR, and to increase Qmax even in patients with prostate volumes of between 30 and 40 mL [170, 171]. A long-term trial with dutasteride in symptomatic men with prostate volumes > 30 mL and increased risk for disease progression showed that dutasteride reduced LUTS at least as much as the α1-blocker tamsulosin [147, 167, 172]. The greater the baseline prostate volume (or serum PSA level), the faster and more pronounced the symptomatic benefit of dutasteride as compared to tamsulosin. 5α-reductase inhibitors, but not α1-blockers, reduce the long-term (> 1 year) risk of AUR or need for surgery [65, 165, 173]. In the PLESS study, finasteride reduced the relative risk of AUR by 57% and need for surgery by 55% (absolute risk reduction 4% and 7%, respectively) at four years, compared with placebo [165]. In the MTOPS study, finasteride reduced the relative risk of AUR by 68% and need for surgery by 64% (absolute risk reduction 2% and 3%, respectively), also at four years [65]. A pooled analysis of three randomised trials with two-year follow-up data, reported that treatment with finasteride decreased the relative risk of AUR by 57%, and surgical intervention by 34% (absolute risk reduction 2% for both) in patients with moderately symptomatic LUTS [174]. Dutasteride has also demonstrated efficacy in reducing the risks for AUR and BPO-related surgery. Open-label trials have demonstrated relevant changes in urodynamic parameters [175, 176]. Furthermore, finasteride might reduce blood loss during transurethral prostate surgery, probably due to its effects on prostatic vascularisation [177, 178].

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Tolerability and safety: The most common adverse events are reduced libido, erectile dysfunction (ED) and less frequently, ejaculation disorders such as retrograde ejaculation, ejaculation failure, or decreased semen volume [65, 148, 160, 179]. Gynaecomastia (with breast or nipple tenderness) develops in 1-2% of patients. Two studies have suggested that treatment with 5-ARIs is associated with a higher incidence of high-grade cancers although no causal relationship has been proven [180, 181]. There is a long-standing debate regarding potential cardiovascular side effects of 5-ARIs, in particular dutasteride [182]. Population-based studies in Taiwan and Ontario did not find an association between the use of 5-ARIs and increased cardiovascular side effects [182, 183]. Practical considerations: Treatment with 5-ARIs should be considered in men with moderate-to-severe LUTS and an enlarged prostate (> 40 mL) and/or elevated PSA concentration (> 1.4-1.6 ng/mL). They can reduce the risk of AUR and need for surgery. Due to the slow onset of action, they are not suitable for short-term use. Their effect on PSA needs to be considered in relation to PCa screening. Summary of evidence After two to four years of treatment, 5-ARIs improve IPSS by approximately 15-30%, decrease prostate volume by 18-28%, and increase Qmax by 1.5-2.0 mL/s in patients with LUTS due to prostate enlargement. 5α-reductase inhibitors can prevent disease progression with regard to AUR and the need for surgery. Due to 5-ARIs slow onset of action, they are suitable only for long-term treatment (years). The most relevant adverse effects of 5-ARIs are related to sexual function, and include reduced libido, ED and less frequently, ejaculation disorders such as retrograde ejaculation, ejaculation failure, or decreased semen volume. Recommendations Use 5α-reductase inhibitors in men who have moderate-to-severe LUTS and an increased risk of disease progression (e.g. prostate volume > 40 mL). Counsel patients about the slow onset of action of 5α-reductase inhibitors.

LE 1b

1a 1b

Strength rating Strong Strong

5.2.3 Muscarinic receptor antagonists Mechanism of action: The detrusor is innervated by parasympathetic nerves whose main neurotransmitter is acetylcholine, which stimulates muscarinic receptors (M-cholinoreceptors) on the smooth muscle cells. Muscarinic receptors are also present on other cell types, such as bladder urothelial cells and epithelial cells of the salivary glands. Five muscarinic receptor subtypes (M1-M5) have been described, of which M2 and M3 are predominant in the detrusor. The M2 subtype is more numerous, but the M3 subtype is functionally more important in bladder contractions [184, 185]. Antimuscarinic effects might also be induced or modulated through other cell types, such as the bladder urothelium or by the central nervous system [186, 187]. The following muscarinic receptor antagonists are licensed for treating OAB/storage symptoms: darifenacin hydrobromide (darifenacin); fesoterodine fumarate (fesoterodine); oxybutynin hydrochloride (oxybutynin); propiverine hydrochloride (propiverine); solifenacin succinate (solifenacin); tolterodine tartrate (tolterodine); and trospium chloride. Transdermal preparations of oxybutynin have been formulated and evaluated in clinical trials [188, 189]. Efficacy: Antimuscarinics were mainly tested in females in the past, as it was believed that LUTS in men were caused by the prostate, so should be treated with prostate-specific drugs. However, there is no scientific data for this assumption [190]. A sub-analysis of an open-label trial of OAB patients showed that age, but not gender had an impact on urgency, frequency, or urgency incontinence [191]. In a pooled analysis, which included a sub-analysis of male patients, fesoterodine 8 mg was superior to tolterodine extended release (ER) 4 mg for the improvement of severe urgency episodes/24 hours and the OAB-q Symptom Bother score at week twelve, the urinary retention rate was around 2% [192]. The efficacy of antimuscarinics as single agents in men with OAB in the absence of BOO have been tested [193-198]. Most trials lasted only twelve weeks. Four post hoc analyses of large RCTs on the treatment of OAB in women and men without presumed BOO were performed focusing only on the men [190, 194, 199]. Tolterodine can significantly reduce urgency incontinence, daytime or 24-hour frequency and urgency-related voiding whilst improving patient perception of treatment benefit. Solifenacin significantly improved mean patient perception of bladder condition scores, mean OAB questionnaire scores, and overall perception of bladder problems. Fesoterodine improved micturition frequency, urgency episodes, and urgency urinary incontinence (UUI) episodes. In open-label trials with tolterodine, daytime frequency, nocturia, UUI, and

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IPSS were significantly reduced compared with baseline values after 12-25 weeks [195, 198]. The TIMES RCT reported that tolterodine ER monotherapy significantly improved UUI episodes per 24 hours compared to placebo, at week twelve. Tolterodine ER did not significantly improve urgency, IPSS total or QoL score compared with placebo. A significantly greater proportion of patients in the tolterodine ER plus tamsulosin group reported treatment benefit compared with the other three treatment groups [197]. A further analysis showed that men with PSA levels of < 1.3 ng/mL (smaller prostates) might benefit more from antimuscarinics [200]. Two other studies found a positive effect of antimuscarinics in patients with OAB and concomitant BPO [198, 201]. In a small RCT propiverine improved frequency and urgency episodes [201]. Tolerability and safety: Antimuscarinic drug trials generally show approximately 3-10% withdrawals, which is similar to placebo. Drug-related adverse events include dry mouth (up to 16%), constipation (up to 4%), micturition difficulties (up to 2%), nasopharyngitis (up to 3%), and dizziness (up to 5%). Increased PVR in men without BOO is minimal and similar to placebo. Nevertheless, fesoterodine 8 mg showed higher PVRs (+20.2 mL) than placebo (-0.6 mL) or fesoterodine 4 mg (+9.6 mL) [195]. Incidence of urinary retention in men without BOO was similar to placebo for tolterodine (0-1.3% vs. 0-1.4%). With fesoterodine 8 mg, 5.3% had symptoms, which was higher than placebo or fesoterodine 4 mg (both 0.8%). These symptoms appeared during the first two weeks of treatment and mainly affected men aged 66 years or older. Theoretically antimuscarinics might decrease bladder strength, and hence might be associated with PVR urine or urinary retention. A twelve week safety study on men with mild-to-moderate BOO showed that tolterodine increased the PVR (49 mL vs. 16 mL) but not AUR (3% in both arms) [202]. The urodynamic effects included larger bladder volumes at first detrusor contraction, higher maximum cystometric capacity, and decreased bladder contractility index, Qmax was unchanged. This trial indicated that short-term treatment with antimuscarinics in men with BOO is safe [190]. Practical considerations: Not all antimuscarinics have been tested in elderly men, and long-term studies on the efficacy of muscarinic receptor antagonists in men of any age with LUTS are not yet available. In addition, only patients with low PVR volumes at baseline were included in the studies. These drugs should therefore be prescribed with caution, and regular re-evaluation of IPSS and PVR urine is advised. Men should be advised to discontinue medication if worsening voiding LUTS or urinary stream is noted after initiation of therapy. Summary of evidence LE Antimuscarinic monotherapy can significantly improve urgency, UUI, and increased daytime frequency. 2 Antimuscarinic monotherapy can be associated with increased PVR after therapy, but acute retention 2 is a rare event in men with a PVR volume of < 150 mL at baseline. Recommendations Use muscarinic receptor antagonists in men with moderate-to-severe LUTS who mainly have bladder storage symptoms. Do not use antimuscarinic overactive bladder medications in men with a post-void residual volume > 150 mL.

Strength rating Strong Weak

5.2.4 Beta-3 agonist Mechanism of action: Beta-3 adrenoceptors are the predominant beta receptors expressed in the smooth muscle cells of the detrusor and their stimulation is thought to induce detrusor relaxation. The mode of action of beta-3 agonists is not fully elucidated [203]. Efficacy: Mirabegron 50 mg is the first clinically available beta-3 agonist with approval for use in adults with OAB. Mirabegron has undergone extensive evaluation in RCTs conducted in Europe, Australia, North America and Japan [204-208]. Mirabegron demonstrated significant efficacy in treating the symptoms of OAB, including micturition frequency, urgency and UUI and also patient perception of treatment benefit. These studies had a predominantly female study population. A meta-analysis of eight RCTS including 10,248 patients (27% male) found that mirabegron treatment resulted in reduced frequency, urgency and UUI rates, as well as an improved voided volume with a statistically significant improvement of nocturia as compared with both placebo and tolterodine [209]. Mirabegron has been evaluated in male patients with OAB in the context of LUTS either associated with or not associated with BPO confirmed by urodynamics [210]. Mirabegron 25 mg daily led to increased satisfaction and improved QoL, but symptoms assessed by validated questionnaires (IPSS and OAB-SS), only

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improved in non-obstructed patients. Mirabegron as an add-on therapy has been studied in OAB patients with incontinence despite antimuscarinic therapy [211], again in a predominantly female study population. An Asian study with a higher proportion of male subjects (approximately one third) reported superiority over placebo in reducing frequency of micturition, but did not report the results separately for the genders [212]. In a study of more than 1,000 patients of whom approximately 30% were male, combination therapy of mirabegron 25/50 mg and solifenacin 5/10 mg was associated with statistically significant improvements in patient outcomes and health related QoL vs. solifenacin 5 mg and placebo; however, they did not separate out the effects in men and women [213]. In another study, in which 28% patients were male, mirabegron significantly improved patient reported perception of their condition and QoL whether or not patients were incontinent [214]. A phase IV study, with a small proportion of male subjects, reported addition of mirabegron in people with persisting urgency despite solifenacin in a Japanese population [215]. In an RCT evaluating add-on therapy with mirabegron for OAB symptoms remaining after treatment with tamsulosin 0.2 mg daily in men with BPO, combination therapy was associated with greater improvements in OAB symptom score, in the urinary urgency and daytime frequency part and storage subscore of the IPSS, and in the QoL index compared to monotherapy with tamsulosin [216]. A prospective analysis of 50 elderly men showed that mirabegron add-on therapy was effective for patients whose persistent LUTS and OAB symptoms were not controlled with α1-blocker monotherapy, without causing negative effects on voiding function [217]. An RCT compared the efficacy of mirabegron 50 mg or fesoterodine 4 mg add-on therapy to silodosin in LUTS patients with persisting OAB symptoms [218]. At three months, fesoterodine add-on therapy showed a significantly greater improvement then mirabegron add-on therapy in OAB symptom score-total (-2.8 vs. -1.5, p = 0.004), IPSS-QoL (-1.5 vs. -1.1, p = 0.04), and OAB symptom score-urgency score (-1.5 vs. -0.9, p = 0.008). Fesoterodine was also superior in alleviating detrusor overactivity (52.6% vs. 28.9%, p = 0.03). Tolerability and safety: The most common treatment-related adverse events in the mirabegron groups were hypertension, UTI, headache and nasopharyngitis [204-207]. Mirabegron is contraindicated in patients with severe uncontrolled hypertension (systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg, or both). Blood pressure should be measured before starting treatment and monitored regularly during treatment. A combination of thirteen clinical studies including 13,396 patients, 25% of whom were male, showed that OAB treatments (anticholinergics or mirabegron) were not associated with an increased risk of hypertension or cardiovascular events compared to placebo [219]. The proportion of patients with dry mouth and constipation in the mirabegron groups was notably lower than reported in RCTs of other OAB agents or of the active control tolterodine [204]. Evaluation of urodynamic parameters in men with combined BOO and OAB concluded that mirabegron did not adversely affect voiding urodynamic parameters compared to placebo in terms of Qmax, detrusor pressure at maximum flow and bladder contractility index [220]. The overall change in PVR with mirabegron is small [220]. A small prospective study (mainly focused on males) has shown that mirabegron 25 mg is safe in patients aged 80 years or more with multiple comorbidities [221]. A pooled analysis of three trials each of twelve weeks and a one year trial showed, in patients aged > 65 years, a more favourable tolerability profile for mirabegron than antimuscarinics [222]. In an eighteen week study of 3,527 patients (23% male), the incidence of adverse events were higher in the combination (solifenacin 5 mg plus mirabegron 25 mg) group (40%) than the mirabegron 25 mg alone group (32%). Events recorded as urinary retention were low (< 1%), but were reported slightly more frequently in the combined group when compared with the monotherapy and placebo groups. The PVR volume was slightly increased in the combined group compared with solifenacin 5 mg, and the mirabegron monotherapy and placebo groups. Combined therapy with solifenacin 5 mg plus mirabegron 25 mg and solifenacin 5 mg plus mirabegron 50 mg provided improvements in efficacy generally consistent with an additive effect [223]. In a retrospective analysis of persistence and adherence in 21,996 patients, of whom 30% were male, the median time to discontinuation was significantly longer for mirabegron (169 days) compared to tolterodine (56 days) and other antimuscarinics (30-78 days) (p < 0.0001). There was no statistical difference between men and women [224]. Data on the safety of combination therapy at twelve months are awaited from the SYNERGY II trial. Practical considerations: Long-term studies on the efficacy and safety of mirabegron in men of any age with LUTS are not yet available. Studies on the use of mirabegron in combination with other pharmacotherapeutic agents for male LUTS are pending. However, pharmacokinetic interaction upon add-on of mirabegron or tamsulosin to existing tamsulosin or mirabegron therapy does not cause clinically relevant changes in safety profiles [225]. Available studies on mirabegron in combination with antimuscarinics in OAB patients had a predominantly female study population, while further trials are still pending.

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Summary of evidence Mirabegron improves the symptoms of OAB, including micturition frequency, urgency and UUI. Patients prescribed mirabegron remained on treatment longer than those prescribed antimuscarinics. Recommendation Use beta-3 agonists in men with moderate-to-severe LUTS who mainly have bladder storage symptoms.

LE 2 3

Strength rating Weak

5.2.5 Phosphodiesterase 5 inhibitors Mechanism of action: Phosphodiesterase 5 inhibitors (PDE5Is) increase intracellular cyclic guanosine monophosphate, thus reducing smooth muscle tone of the detrusor, prostate and urethra. Nitric oxide and PDE5Is might also alter reflex pathways in the spinal cord and neurotransmission in the urethra, prostate, or bladder [226]. Moreover, chronic treatment with PDE5Is seems to increase blood perfusion and oxygenation in the LUT [227]. Phosphodiesterase 5 inhibitors could also reduce chronic inflammation in the prostate and bladder [228]. The exact mechanism of PDE5Is on LUTS remains unclear. Although clinical trials of several selective oral PDE5Is have been conducted in men with LUTS, only tadalafil (5 mg once daily) has been licensed for the treatment of male LUTS. Efficacy: Several RCTs have demonstrated that PDE5Is reduce IPSS, storage and voiding LUTS, and improve QoL. However, Qmax did not significantly differ from placebo in most trials. A recent Cochrane review included a total of sixteen randomised trials that examined the effects of PDE5Is compared to placebo and other standard of care drugs (α1-blockers and 5-ARIs) in men with LUTS [229]. Phosphodiesterase 5 inhibitors led to a small reduction (mean difference (MD) 1.89 lower, 95% CI 2.27 lower to 1.50 lower) in IPSS compared to placebo. There was no difference between PDE5Is and α1-blockers in IPSS. Most evidence was limited to short-term treatment up to twelve weeks and of moderate or low certainty. In earlier [230] and more recent [231] meta-analysis, PDE5Is were also found to improve IPSS and IIEF score, but not Qmax. Tadalafil 5 mg reduces IPSS by 22-37% and improvement may be seen within a week of initiation of treatment [232]. A three point or greater total IPSS improvement was observed in 60% of tadalafil treated men within one week and in 80% within four weeks [233]. The maximum trial (open label) duration was 52 weeks [234]. A subgroup analysis of pooled data from four RCTs demonstrated a significant reduction in LUTS, regardless of baseline severity, age, previous use of α-blockers or PDE5Is, total testosterone level or predicted prostate volume [235]. In a recent post hoc analysis of pooled data from four RCTs, tadalafil was shown to also be effective in men with cardiovascular risk factors/comorbidities, except for patients receiving more than one antihypertensive medication. The use of diuretics may contribute to patients’ perception of a negated efficacy [236]. Among sexually active men > 45 years with comorbid LUTS/BPH and ED, tadalafil improved both conditions [235]. An integrated data analyses from four placebo controlled clinical studies showed that total IPSS improvement was largely attributed to direct (92.5%, p < 0.001) vs. indirect (7.5%, p = 0.32) treatment effects via IIEF-EF improvement [237]. Another analysis showed a small but significant increase in Qmax without any effect on PVR [238]. An integrated analysis of RCTs showed that tadalfil was not superior to placebo for IPSS improvement at twelve weeks in men ≥ 75 years (with varied effect size between studies), but was for men < 75 years [239]. An open label urodynamic study of 71 patients showed improvements in both voiding and storage symptoms, confirmed by improvements in BOO index (61.3 to 47.1; p < 0.001), and resolution of DO in 15 (38%) of 38 patients. Flow rate improved from 7.1 to 9.1 mL/s (p < 0.001) and mean IPSS from 18.2 to 13.4 [240]. A combination of PDE5Is and α-blockers has also been evaluated. A meta-analysis of five RCTs (two studies with tadalafil 20 mg, two with sildenafil 25 mg, and one with vardenafil 20 mg), showed that combination therapy significantly improved IPSS score (-1.8), IIEF score (+3.6) and Qmax (+1.5 mL/s) compared with α-blockers alone [230]. A Cochrane review found similar findings [229]. The effects of tadalafil 5 mg combined with finasteride 5 mg were assessed in a 26-week placebo-controlled RCT [241]. The combination of tadalafil and finasteride provided an early improvement in urinary symptoms (p < 0.022 after 4, 12 and 26 weeks), with a significant improvement of storage and voiding symptoms and QoL. Combination therapy was well tolerated and improved erectile function [241]. However, only tadalafil 5 mg has been licensed in the context of LUTS management while data on combinations of PDE5Is and other LUTS medications is emerging. Tolerability and safety: Reported adverse effects in RCTs comparing the effect of all PDE5Is vs. placebo in men with LUTS include flushing, gastroesophageal reflux, headache, dyspepsia, back pain and nasal congestion [230]. The discontinuation rate due to adverse effects for tadalafil was 2.0% [242] and did not differ by age, LUTS severity, testosterone levels, or prostate volume in the pooled data analyses [235].

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Phosphodiesterase 5 inhibitors are contraindicated in patients using nitrates, the potassium channel opener nicorandil, or the α1-blockers doxazosin and terazosin. They are also contraindicated in patients who have unstable angina pectoris, have had a recent myocardial infarction (< three months) or stroke (< six months), myocardial insufficiency (New York Heart Association stage > 2), hypotension, poorly controlled blood pressure, significant hepatic or renal insufficiency, or if anterior ischaemic optic neuropathy with sudden loss of vision is known or was reported after previous use of PDE5Is. Practical considerations: To date, only tadalafil 5 mg once daily has been officially licensed for the treatment of male LUTS with or without ED. The meta-regression suggested that younger men with low body mass index and more severe LUTS benefit the most from treatment with PDE5Is [230]. Long-term experience with tadalafil in men with LUTS is limited to one trial with a one year follow-up [234]; therefore, conclusions about its efficacy or tolerability greater than one year are not possible. There is limited information on reduction of prostate size and no data on disease progression. Summary of evidence LE 1a Phosphodiesterase 5 inhibitors improve IPSS and IIEF score, but not Qmax . A three point or greater total IPSS improvement was observed in 59.8% of tadalafil treated men within 1b one week and in 79.3% within four weeks. Recommendation Use phosphodiesterase type 5 inhibitors in men with moderate-to-severe LUTS with or without erectile dysfunction.

Strength rating Strong

5.2.6 Plant extracts - phytotherapy Potential mechanism of action: Herbal drug preparations are made of roots, seeds, pollen, bark, or fruits. There are single plant preparations (mono-preparations) and preparations combining two or more plants in one pill (combination preparations) [243]. Possible relevant compounds include phytosterols, ß-sitosterol, fatty acids, and lectins [243]. In vitro, plant extracts can have anti-inflammatory, anti-androgenic and oestrogenic effects; decrease sexual hormone binding globulin; inhibit aromatase, lipoxygenase, growth factor-stimulated proliferation of prostatic cells, α-adrenoceptors, 5 α-reductase, muscarinic cholinoceptors, dihydropyridine receptors and vanilloid receptors; and neutralise free radicals [243-245]. The in vivo effects of these compounds are uncertain, and the precise mechanisms of plant extracts remain unclear. Efficacy: The extracts of the same plant produced by different companies do not necessarily have the same biological or clinical effects; therefore, the effects of one brand cannot be extrapolated to others [246]. In addition, batches from the same producer may contain different concentrations of active ingredients [247]. A review of recent extraction techniques and their impact on the composition/biological activity of available Serenoa repens based products showed that results from different clinical trials must be compared strictly according to the same validated extraction technique and/or content of active compounds [248], as the pharmacokinetic properties of the different preparations can vary significantly. Heterogeneity and a limited regulatory framework characterise the current status of phytotherapeutic agents. The European Medicines Agency (EMA) has developed the Committee on Herbal Medicinal Products (HMPC). European Union (EU) herbal monographs contain the HMPC’s scientific opinion on safety and efficacy data about herbal substances and their preparations intended for medicinal use. The HMPC evaluates all available information, including non-clinical and clinical data, whilst also documenting longstanding use and experience in the EU. European Union monographs are divided into two sections: a) Well established use (marketing authorisation): when an active ingredient of a medicine has been used for more than ten years and its efficacy and safety have been well established (including a review of the relevant literature); and b) Traditional use (simplified registration): for herbal medicinal products which do not fulfil the requirements for a marketing authorisation, but there is sufficient safety data and plausible efficacy on the basis of longstanding use and experience. Table 1 lists the available EU monographs for herbal medicinal products.

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Table 2: European Union monographs for herbal medicinal products Herbal substance

HMPC evaluation

Therapeutic Indication by HMPC Symptomatic treatment of BPH

Date of monograph

Serenoa repens, fructus (saw palmetto, fruit) Extraction solvent: hexane [1] Serenoa repens, fructus (saw palmetto, fruit) Extraction solvent: ethanol [1] Cucurbita pepo L, semen (pumpkin seed) Preparation as defined in the monograph [249] Prunus africana (Hook f.) Kalkm., cortex (pygeum africanum bark) Preparation as defined in the monograph [250] Urtica dioica L., Urtica urens L., their hybrids or their mixtures, radix Preparation as defined in the monograph [251] Epilobium angustifolium L. and/or Epilobium parviflorum Schreb., herba (Willow herb) Preparation as defined in the monograph [252]

Well established use

Traditional use

LUTS related to BPH*

14/01/2016

Traditional use

LUTS related to BPH or related to an OAB*

25/03/2013

Traditional use

LUTS related to BPH*

01/09/2017

Traditional use

LUTS related to BPH*

05/11/2012

Traditional use

LUTS related to BPH*

13/01/2016

14/01/2016

*After serious conditions have been excluded by a medical doctor. Panel interpretation: Only hexane extracted Serenoa repens (HESr) has been recommended for wellestablished use by the HMPC. Based on this a detailed scoping search covering the timeframe between the search cut-off date of the EU monograph and April 2020 was conducted for HESr. A large meta-analysis of 30 RCTs with 5,222 men and follow-up ranging from 4 to 60 weeks, demonstrated no benefit of treatment with S. repens in comparison to placebo for the relief of LUTS [253]. It was concluded that S. repens was not superior to placebo, finasteride, or tamsulosin with regard to IPSS improvement, Qmax, or prostate size reduction; however, the similar improvement in IPSS or Qmax compared with finasteride or tamsulosin could be interpreted as treatment equivalence. Importantly, in the meta-analysis all different brands of S. repens were included regardless or not of the presence of HESr as the main ingredient in the extract. Another SR focused on data from twelve RCTs on the efficacy and safety of HESr [254]. It was concluded that HESr was superior to placebo in terms of improvement of nocturia and Qmax in patients with enlarged prostates. Improvement in LUTS was similar to tamsulosin and short-term use of finasteride. An updated SR analysed fifteen RCTs and also included twelve observational studies. It confirmed the results of the previous SR on the efficacy of HESr [255]. Compared with placebo, HESr was associated with 0.64 (95% CI 0.98 to 0.31) fewer voids/night and an additional mean increase in Qmax of 2.75 mL/s (95% CI 0.57 to 4.93), both were significant. When compared with α-blockers, HESr showed similar improvements in IPSS (WMD 0.57, 95% CI 0.27 to 1.42) and a comparable increase in Qmax when compared to tamsulosin (WMD 0.02, 95% CI 0.71 to 0.66). Efficacy assessed using IPSS was similar after six months of treatment between HESr and 5-ARIs. Analysis of all available published data for HESr showed a mean significant improvement in IPSS from baseline of 5.73 points (95% CI 6.91 to 4.54) [255]. A network meta-analysis tried to compare the clinical efficacy of S. repens (HESr and non-HESr) against placebo and α1-blockers in men with LUTS. Interestingly, only two RCTs on HESr were included in the analysis. It was found that S. repens achieved no clinically meaningful improvement against placebo or α1-blockers in short-term follow-up. However, S. repens showed a clinical benefit after a prolonged period of treatment, and HESr demonstrated a greater improvement than non-HESr in terms of IPSS [256]. With respect to safety and tolerability, data from the SRs showed that HESr had a favourable safety profile with gastrointestinal disorders being the most frequent adverse effects (mean incidence 3.8%) while HESr had very limited impact on sexual function.

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A cross-sectional study compared the combination of HESr with silodosin to silodosin monotherapy in patients treated for at least twelve months (mean duration 13.5 months) [257]. It was reported that 69.9% of the combination therapy patients achieved the predefined clinically meaningful improvement (improvement more than three points in baseline IPSS) compared to 30.1% of patients treated only with silodosin. In addition, a greater than 25% improvement in IPSS was found in 68.8% and 31.2% of the patients in the combination and the monotherapy groups, respectively. These data suggest that combination of a α1-blocker with HESr may result in greater clinically meaningful improvements in LUTS compared to α1-blocker monotherapy [257]. Practical considerations: Available RCTs do not use the same endpoints (e.g. IPSS). More studies on the use of HESr in combination with other pharmacotherapeutic agents for male LUTS are pending. There is a need to define the subpopulation of patients who will benefit most from therapy with HESr. Summary of evidence HESr improves Qmax and results in fewer voids/night [0.64 (95% CI 0.98 to 0.31)] compared to placebo. HESr has a very limited negative impact on sexual function. Recommendations Offer hexane extracted Serenoa repens to men with LUTS who want to avoid any potential adverse events especially related to sexual function. Inform the patient that the magnitude of efficacy may be modest.

LE 2 2

Strength rating Weak Strong

5.2.7 Combination therapies 5.2.7.1 α1-blockers + 5α-reductase inhibitors Mechanism of action: Combination therapy consists of an α1-blocker (Section 5.2.1) together with a 5-ARI (Section 5.2.2). The α1-blocker exhibits clinical effects within hours or days, whereas the 5-ARI needs several months to develop full clinical efficacy. Finasteride has been tested in clinical trials with alfuzosin, terazosin, doxazosin or terazosin, and dutasteride with tamsulosin. Efficacy: Several studies have investigated the efficacy of combination therapy against an α1-blocker, 5-ARI or placebo alone. Initial studies with follow-up periods of six to twelve months demonstrated that the α1-blocker was superior to finasteride in symptom reduction, whereas combination therapy of both agents was not superior to α1-blocker monotherapy [162, 163, 258]. In studies with a placebo arm, the α1-blocker was consistently more effective than placebo, but finasteride was not. Data at one year in the MTOPS study showed similar results [65]. Long-term data (four years) from the MTOPS and CombAT studies showed that combination treatment is superior to monotherapy for symptoms and Qmax, and superior to α1-blocker alone in reducing the risk of AUR or need for surgery [65, 147, 148]. The CombAT study demonstrated that combination treatment is superior to either monotherapy regarding symptoms and flow rate starting from month nine, and superior to α1-blocker for AUR and the need for surgery after eight months [148]. Thus, the differences in MTOPS may reflect different inclusion and exclusion criteria and baseline patient characteristics. Discontinuation of the α1-blocker after six to nine months of combination therapy was investigated by an RCT and an open-label multicentre trial [259, 260]. The first trial evaluated the combination of tamsulosin with dutasteride and the impact of tamsulosin discontinuation after six months [259], with almost three quarters of patients reporting no worsening of symptoms. However, patients with severe symptoms (IPSS > 20) at baseline may benefit from longer combination therapy. A more recent trial evaluated the symptomatic outcome of finasteride monotherapy at three and nine months after discontinuation of nine-month combination therapy [260]. Lower urinary tract symptom improvement after combination therapy was sustained at three months (IPSS difference 1.24) and nine months (IPSS difference 0.4). The limitations of the studies include the short duration of the studies and the short follow-up period after discontinuation. In both the MTOPS and CombAT studies, combination therapy was superior to monotherapy in preventing clinical progression as defined by an IPSS increase of at least four points, AUR, UTI, incontinence, or an increase in creatinine > 50%. The MTOPS study found that the risk of long-term clinical progression (primarily due to increasing IPSS) was reduced by 66% with combined therapy vs. placebo and to a greater extent than with either finasteride or doxazosin monotherapy (34% and 39%, respectively) [65]. In addition, finasteride (alone or in combination), but not doxazosin alone, significantly reduced both the risks of AUR and the need

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for BPO-related surgery over the four-year study. In the CombAT study, combination therapy reduced the relative risks of AUR by 68%, BPO-related surgery by 71%, and symptom deterioration by 41% compared with tamsulosin, after four years [261]. To prevent one case of urinary retention and/or surgical treatment thirteen patients need to be treated for four years with dutasteride and tamsulosin combination therapy compared to tamsulosin monotherapy while the absolute risk reduction (risk difference) was 7.7%. The CONDUCT study compared efficacy and safety of a fixed-dose combination of dutasteride and tamsulosin to a WW approach with the potential initiation of tamsulosin (step-up approach) in a two year RCT with a total of 742 patients. In both arms detailed lifestyle advice was given. This fixed-dose combination resulted in a rapid and sustained improvement in men with moderate LUTS at risk of disease progression, the difference in IPSS at 24 months was 5.4 in the active arm and 3.6 in the placebo arm (p < 0.001) [262]. Furthermore, tamsulosin plus dutasteride significantly reduced the relative risk of clinical progression (mainly characterised as a worsening in symptoms) by 43.1% when compared with WW, with an absolute risk reduction of 11.3% (number needed to treat [NNT] = 9). The influence of baseline variables on changes in IPSS after combination therapy with dutasteride plus tamsulosin or either monotherapy was tested based on the four year results of the CombAT study. Combination therapy provided consistent improvement of LUTS over tamsulosin across all analysed baseline variables at 48 months [263]. More recently, a combination of the 5-ARI finasteride and tadalafil 5 mg was tested in a large scale RCT against finasteride monotherapy. This study supports the concept of this novel combination therapy and is described in more detail in the chapter on PDE5Is [241]. Tolerability and safety: Adverse events for both drug classes have been reported with combination treatment [65, 147, 148]. The adverse events observed during combination treatment were typical of α1-blockers and 5-ARIs. The frequency of adverse events was significantly higher for combination therapy. The MTOPS study demonstrated that the incidence of treatment related adverse events is higher during the first year of combined treatment between doxazosin and finasteride [264]. A meta-analysis measuring the impact of medical treatments for LUTS/BPH on ejaculatory function, reported that combination therapy with α1-blockers and 5-ARIs resulted in a three-fold increased risk of EjD as compared with each of the monotherapies [157]. Practical considerations: Compared with α1-blockers or 5-ARI monotherapy, combination therapy results in a greater improvement in LUTS and increase in Qmax and is superior in prevention of disease progression. However, combination therapy is also associated with a higher rate of adverse events. Combination therapy should therefore be prescribed primarily in men who have moderate-to-severe LUTS and are at risk of disease progression (higher prostate volume, higher PSA concentration, advanced age, higher PVR, lower Qmax, etc.). Combination therapy should only be used when long-term treatment (more than twelve months) is intended and patients should be informed about this. Discontinuation of the α1-blocker after six months might be considered in men with moderate LUTS. Summary of evidence Long-term data (four years) from the MTOPS and CombAT studies showed that combination treatment is superior to monotherapy for symptoms and Qmax, and superior to α1-blocker alone in reducing the risk of AUR or need for surgery. The MTOPS study found that the risk of long-term clinical progression (primarily due to increasing IPSS) was reduced by 66% with combined therapy vs. placebo and to a greater extent than with either finasteride or doxazosin monotherapy. The CombAT study found that combination therapy reduced the relative risks of AUR by 68%, BPHrelated surgery by 71%, and symptom deterioration by 41% compared with tamsulosin, after four years. Adverse events of both drug classes are seen with combined treatment using α1-blockers and 5-ARIs. Recommendation Offer combination treatment with an α1-blocker and a 5α-reductase inhibitor to men with moderate-to-severe LUTS and an increased risk of disease progression (e.g. prostate volume > 40 mL).

LE 1b

1b

1b 1b

Strength rating Strong

5.2.7.2 α1-blockers + muscarinic receptor antagonists Mechanism of action: Combination treatment consists of an α1-blocker together with an antimuscarinic aiming to antagonise both α1-adrenoceptors and muscarinic receptors. The possible combinations have not all been tested in clinical trials yet.

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Efficacy: Several RCTs and prospective studies investigated combination therapy, lasting four to twelve weeks, either as an initial treatment in men with OAB and presumed BPO or as a sequential treatment for storage symptoms persisting while on an α1-blocker [197, 261, 265-271]. One trial used the α1-blocker naftopidil (not registered in most European countries) with and without antimuscarinics [272]. A high proportion of men with voiding and storage LUTS need to add anticholinergics after α1-blocker monotherapy, particularly those with longer duration of symptoms at presentation, and men with storage symptoms and a small prostate volume [273]. Combination treatment is more efficacious in reducing urgency, UUI, voiding frequency, nocturia, or IPSS compared with α1-blockers or placebo alone, and improves QoL [197, 274]. Symptom improvement is higher regardless of PSA concentration with combination therapy, whereas tolterodine alone improved symptoms mainly in men with a serum PSA of < 1.3 ng/mL [200]. Persistent LUTS during α1-blocker treatment can be reduced by the additional use of an antimuscarinic, [261, 265, 271, 275, 276]. Two SRs of the efficacy and safety of antimuscarinics in men suggested that combination treatment provides significant benefit [277, 278]. In a meta-analysis of sixteen studies with 3,548 patients with BPH/OAB, initial combination treatment of an α1-blocker with anticholinergic medication improvement storage symptoms and QoL compared to α1-blocker monotherapy without causing significant deterioration of voiding function [279]. There was no difference in total IPSS and Qmax between the two groups. Effectiveness of therapy is evident primarily in those men with moderate-to-severe storage LUTS [280]. Long term use of combination therapy has been reported in patients receiving treatment for up to one year, showing symptomatic response is maintained, with a low incidence of AUR [281]. In men with moderateto-severe storage symptoms, voiding symptoms and PVR < 150 mL, the reduction in symptoms using combination therapy is associated with patient-relevant improvements in health related quality of life compared with placebo and α1-blocker monotherapy [282]. Tolerability and safety: Adverse events of both drug classes are seen with combined treatment using α1-blockers and antimuscarinics. The most common side-effect is dry mouth. Some side-effects (e.g. dry mouth or ejaculation failure) may show increased incidence which cannot simply be explained by summing the incidence with the drugs used separately. Increased PVR may be seen, but is usually not clinically significant, and risk of AUR is low up to one year of treatment [277, 283]. Antimuscarinics do not cause evident deterioration in maximum flow rate used in conjunction with an α1-blocker in men with OAB symptoms [274, 284]. A recent RCT investigated safety in terms of maximum detrusor pressure and Qmax for solifenacin (6 mg or 9 mg) with tamsulosin in men with LUTS and BOO compared with placebo [285]. The combination therapy was not inferior to placebo for the primary urodynamic variables; Qmax was increased vs. placebo [285]. Practical considerations: Class effects are likely to underlie efficacy and QoL using an α1-blocker and antimuscarinic. Trials used mainly storage symptom endpoints, were of short duration, and included only men with low PVR volumes at baseline. Therefore, measuring PVR is recommended during combination treatment.

Summary of evidence Combination treatment with α1-blockers and antimuscarinics is effective for improving LUTS-related QoL impairment. Combination treatment with α1-blockers and antimuscarinics is more effective for reducing urgency, UUI, voiding frequency, nocturia, or IPSS compared with α1-blockers or placebo alone. Adverse events of both drug classes are seen with combined treatment using α1-blockers and antimuscarinics. There is a low risk of AUR using α1-blockers and antimuscarinics in men known to have a PVR urine volume of < 150 mL.

LE 2 2 1 2

Recommendations Strength rating Strong Use combination treatment of a α1-blocker with a muscarinic receptor antagonist in patients with moderate-to-severe LUTS if relief of storage symptoms has been insufficient with monotherapy with either drug. Do not prescribe combination treatment in men with a post-void residual volume > 150 mL. Weak Note: A  ll patients should be counselled about pharmacological treatment related adverse events in order to select the most appropriate treatment for each individual patient.

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5.3

Surgical treatment

Surgical treatment is one of the cornerstones of LUTS/BPO management. Based on its ubiquitous availability, as well as its efficacy, M-TURP has long been considered as the reference technique for the surgical management of LUTS/BPO. However, in recent years various techniques have been developed with the aim of providing a safe and effective alternative to M-TURP. Previously, the surgical section of the Guidelines was based on technology rather than surgical approach; additionally, most of the studies are restricted by prostate size, which is also reflected in the present Guidelines. Notably, only a small fraction of RCTs are performed in patients with a prostate volume > 80 mL; therefore, high-level evidence for larger prostates is limited. As the clinical reality is primarily reflected by surgical approach and not necessarily by a specific technology, the chapter on surgical management has been restructured. It is now divided into the following five sections: 1. 2. 3. 4. 5.

Resection; Enucleation; Vaporisation; Alternative ablative techniques; and Non-ablative techniques.

Based on Panel consensus, timeframes defining short-, mid- and long-term follow-up of patients submitted to surgical treatments are 12, 36 and over 36 months, respectively. The durability of a technique is reflected by the re-operation rate during follow-up, the failure to wean patients off medication as well as the initiation of novel LUTS medication after surgery. However, for the majority of techniques only the re-operation rate is reported and clinicians should inform patients that long-term surgical RCTs are often lacking. Some patients value sexual function and perceived higher safety than maximum efficacy; therefore, it is not surprising that some patients consciously choose an alternative ablative or non-ablative technique despite the knowledge that it might not be their definitive treatment. In contrast, many urologists are critical about these ‘lesser’ procedures due to their inferior relief of BOO. Recommendations on new devices or interventions will only be included in the Guidelines once supported by a minimum level of evidence. To clarify this the Panel have published their position on certainty of evidence (CoE) [286]. In summary, a device or technology is only included once supported by RCTs looking at both efficacy and safety, with adequate follow-up, and secondary studies to confirm the reproducibility and generalisability of the first pivotal studies [286]. Otherwise, there is a danger that a single pivotal study can be overexploited by device manufacturers. Studies that are needed include (1) proof of concept, (2) RCTs on efficacy and safety, as well as (3) cohort studies with a broad range of inclusion and exclusion criteria to confirm both reproducibility and generalisability of the benefits and harms [286]. The panel assesses the quality of all RCTs and if they do not meet the standard required the intervention will continue to have no recommendation i.e. a RCT does not guarantee inclusion in the Guidelines. In addition, the Guidelines continues to include techniques under investigation. These are devices or technologies that have shown promising results in initial studies; however, they do not meet the aforementioned criteria yet to provide a CoE which allows the Panel to regard these devices or technologies as recommended alternatives. To account for evolving evidence, recommendations for some techniques under investigation have been made; however, these techniques remain under investigation until further studies provide the recommended CoE. 5.3.1 Resection of the prostate 5.3.1.1 Monopolar and bipolar transurethral resection of the prostate Mechanism of action: Transurethral resection of the prostate (TURP) is performed using two techniques: monopolar TURP (M-TURP) and bipolar TURP (B-TURP). Monopolar transurethral resection of the prostate removes tissue from the transition zone of the gland. Bipolar TURP addresses a major limitation of M-TURP by allowing performance in normal saline. Prostatic tissue removal is identical to M-TURP. Contrary to M-TURP, in B-TURP systems, the energy does not travel through the body to reach a skin pad. Bipolar circuitry is completed locally; energy is confined between an active (resection loop) and a passive pole situated on the resectoscope tip (“true” bipolar systems) or the sheath (“quasi” bipolar systems). The various bipolar devices available differ in the way in which current flow is delivered [287, 288]. Efficacy: In a meta-analysis of 20 RCTs with a maximum follow-up of five years, M-TURP resulted in a substantial mean Qmax improvement (+162%), a significant reduction in IPSS (-70%), QoL score (-69%), and PVR (-77%) [289]. Monopolar-TURP delivers durable outcomes as shown by studies with a follow-up of 8-22 years. There are no similar data on durability for any other surgical treatment for BPO [290]. One study with a mean follow-up of thirteen years reported a significant and sustained decrease in most symptoms and improvement in urodynamic parameters. Failures were associated with DUA rather than re-development

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of BPO [102]. A second prostatic operation, usually re-TURP, has been reported at a constant annual rate of approximately 1-2%. A review analysing 29 RCTs found a retreatment rate of 2.6% after a mean follow-up of sixteen months [291]. Data from an Austrian nationwide study of two cohorts totalling 41,059 men submitted to M-TURP showed that the overall retreatment rates (re-TURP, urethrotomy and bladder neck incision) remained unchanged during the last decade (0.9%, 3.7%, 9.5% and 12.7% at three months, one year, five years, and eight years, respectively), and that the respective incidence of re-TURP was 0.8%, 2.4%, 6.1% and 8.3%, respectively [292, 293]. Bipolar TURP is the most widely and thoroughly investigated alternative to M-TURP. Results from 56 RCTs have been reported [294], of which around half have been pooled in RCT-based meta-analyses [289, 295299]. Early pooled results concluded that no clinically relevant differences exist in short-term efficacy (IPSS, QoL score and Qmax) [296]. Subsequent meta-analyses supported these conclusions though trial quality was generally poor [289, 295, 297-299]. Data from RCTs with mid- to long-term follow-up (up to 60 months) showed no differences in efficacy parameters [300-308]. A meta-analysis was conducted to evaluate the quasi-bipolar transurethral resection in saline (TURis, Olympus Medical) system vs. M-TURP. Ten unique RCTs (1,870 patients) were included and it was concluded that TURis was of equivalent efficacy to M-TURP [309]. Tolerability and safety: Peri-operative mortality and morbidity of M-TURP have decreased over time, but morbidity remains considerable (0.1% and 11.1%, respectively) [310]. Data from an Austrian nationwide study of two cohorts totalling 41,059 men submitted to M-TURP showed a 20% reduction in mortality rate over time, to 0.1% at 30 days and 0.5% at 90 days [292, 293]. The risk of TUR-syndrome decreased to < 1.1% [291, 311]. Data from 10,654 M-TURPs reported bleeding requiring transfusion in 2.9% [310]. Short- to mid-term complications reported in an analysis of RCTs using M-TURP as a comparator were: bleeding requiring transfusion 2% (0-9%), TUR-syndrome 0.8% (0-5%), AUR 4.5% (0-13.3%), clot retention 4.9% (0-39%), and UTI 4.1% (0-22%) [289]. Long-term complications of M-TURP comprise urinary incontinence, urinary retention and UTIs, bladder neck contracture (BNC), urethral stricture, retrograde ejaculation and ED [291]. Early pooled results concluded that no differences exist in short-term urethral stricture/BNC rates, but B-TURP is preferable to M-TURP due to a more favourable peri-operative safety profile (elimination of TUR-syndrome; lower clot retention/blood transfusion rates; shorter irrigation, catheterisation, and possibly hospitalisation times) [296]. Subsequent meta-analyses supported these conclusions [289, 295, 297-299]; however, trial quality was relatively poor and limited follow-up might cause under-reporting of late complications, such as urethral stricture/BNC [296]. An RCT based meta-analysis has shown that TURis reduces the risk of TURsyndrome and the need for blood transfusion compared to M-TURP [299]. It was concluded that TURis is associated with improved peri-operative safety, eliminating the risk of TUR syndrome, reducing the risk of blood transfusion/clot retention and hospital stay. No significant difference was detected in urethral stricture rates. Data from the vast majority of individual RCTs with mid- to long-term follow-up (up to 60 months), showed no differences between M-TURP and B-TURP in urethral stricture/BNC rates [300-308], in accordance with all published meta-analyses. However, two individual RCTs have shown opposing results [307, 312]. A significantly higher stricture (urethral stricture + BNC) rate was detected in the B-TURP arm performed with a “quasi” bipolar system (TURis, Olympus Medical) in patients with a prostate volume > 70 mL at 36 months follow-up [307]. In addition, a significantly higher BNC, but not urethral stricture, rate was detected in the B-TURP arm performed with a “true” bipolar system (Gyrus PK SuperPulse, Olympus Medical) in 137 patients followed up to twelve months [312]. Randomised controlled trials using the erectile function domain of the IIEF (IIEF-ED) and the ejaculatory domain of the male sexual-health questionnaire (Ej-MSHQ) showed that M-TURP and B-TURP have a similar effect on erectile and ejaculatory function [313, 314]. Comparative evaluations of the effects on overall sexual function, quantified with IIEF-15, showed no differences between B-TURP and M-TURP at twelve months follow-up (erection, orgasmic function, sexual desire, intercourse satisfaction, overall satisfaction) [314, 315]. Practical considerations: Monopolar-TURP is an effective treatment for moderate-to-severe LUTS secondary to BPO. The choice should be based primarily on prostate volume (30-80 mL suitable for M-TURP). No studies on the optimal cut-off value exist, but the complication rates increase with prostate size [310]. The upper limit for M-TURP is suggested as 80 mL (based on Panel expert opinion, under the assumption that this limit depends on the surgeon’s experience, choice of resectoscope size and resection speed), as surgical duration increases, there is a significant increase in the rate of complications and the procedure is safest when performed in under 90 minutes [316].

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Bipolar TURP in patients with moderate-to-severe LUTS secondary to BPO, has similar efficacy to M-TURP, but lower peri-operative morbidity. The duration of improvements with B-TURP were documented in a number of RCTs with mid-term follow-up. Long-term results (up to five years) for B-TURP showed that safety and efficacy are comparable to M-TURP [300-308]. The choice of B-TURP should be based on equipment availability, surgeon’s experience, and patient’s preference. Summary of evidence Bipolar- or monopolar-TURP is the current standard surgical procedure for men with prostate sizes of 30-80 mL and bothersome moderate-to-severe LUTS secondary of BPO. Bipolar-TURP achieves short-, mid- and long-term results comparable with M-TURP, but B-TURP has a more favourable peri-operative safety profile. Recommendation Offer bipolar- or monopolar-transurethral resection of the prostate to surgically treat moderate-to-severe LUTS in men with prostate size of 30-80 mL.

LE 1a 1a

Strength rating Strong

5.3.1.2 Holmium laser resection of the prostate With the advent of holmium laser enucleation of the prostate (section 5.3.2.3) and the fact that no relevant publications on holmium laser resection of the prostate (HoLRP) have been published since 2004, HoLRP of the prostate does not play a role in contemporary treatment algorithms. 5.3.1.3 Thulium:yttrium-aluminium-garnet laser (Tm:YAG) vaporesection of the prostate Mechanism of action: In the thulium lasers, a wavelength between 1,940 nm (thulium fiber laser) and 2,013 nm (Tm:YAG) is emitted in continuous wave mode. The laser is primarily used in front-fire applications [317]. Different applications such as vaporesection (ThuVARP) have been published [318]. Efficacy: Several meta-analyses with pooled data from both RCTs (generally low quality), and non-RCTs have evaluated ThuVARP vs. M-TURP [319-321], and B-TURP [322-324]. The largest meta-analyses included nine RCTs and seven non-RCTs and reported no clinically relevant differences in efficacy (IPSS, QoL score and Qmax) between ThuVARP and M-TURP or B-TURP at twelve months [323]. Data from one RCT with long-term follow-up showed no difference in efficacy and re-operation rates between ThuVARP and M-TURP (2.1% vs. 4.1%, respectively) [325]. A prospective multicentre study on ThuVARP, including 2,216 patients, showed durable post-operative improvement in IPSS, QoL, Qmax, and PVR for the entire eight years of follow-up [326]. Tolerability and safety: In a number of meta-analyses longer operation times, shorter catheterisation/ hospitalisation times and less blood loss without significant differences in transfusion rates or in any other short-term complication rates have been reported for ThuVARP compared to TURP [319-324]. A significantly higher transfusion rate was reported after M-TURP in two meta-analyses [321, 323]. However, overall RCT quality was relatively low with limited follow-up potentially accounting for under-reporting of late complications, such as urethral stricture/BNC [323]. Data from three RCTs with mid- to long-term follow-up (18 to 48 months) showed no differences in late complication rates between ThuVARP and TURP (BNC: 0.0%-2.1% vs. 0.0%4.1%; stricture: 0.0%-2.2% vs. 0.0%-2.2%, respectively) [325, 327, 328]. Haemoglobin drop was significantly higher in the bridging group in a retrospectively analysed case series of 103 patients who underwent ThuVARP and received either low molecular weight heparin bridging or continued antiplatelet/anticoagulant therapy [329]. Practical considerations: As a limited number of RCTs with mid- to long-term follow-up support the efficacy of ThuVARP, there is a need for ongoing investigation of the technique. Summary of evidence Laser vaporesection of the prostate using Tm:YAG laser (ThuVARP) has longer operation times and shorter catheterisation/hospitalisation times compared to TURP with no clinically relevant differences in short-term efficacy and safety. Mid- to long-term results on efficacy and safety compared to TURP are very limited. Recommendation Offer laser resection of the prostate using Tm:YAG laser (ThuVARP) as an alternative to TURP.

30

LE 1a

Strength rating Weak

MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021

5.3.1.4 Transurethral incision of the prostate Mechanism of action: Transurethral incision of the prostate (TUIP) involves incising the bladder outlet without tissue removal. Transurethral incision of the prostate is conventionally performed with Collins knife using monopolar electrocautery; however, alternative energy sources such as holmium laser may be used [330]. This technique may replace M-TURP in selected cases, especially in prostate sizes < 30 mL without a middle lobe. Efficacy: An RCT comparing conventional TUIP vs. TUIP using holmium laser in prostates ≤ 30 mL with a follow-up of twelve months, found both procedures to be equally effective in relieving BOO with similarly low re-operation rates [330]. A meta-analysis of ten RCTs found similar LUTS improvements and lower but significant improvements in Qmax for TUIP [331]. In this meta-analysis, an upper limit of prostate size was reported as an entry criterion for eight studies with five < 30 mL and three < 60 mL. A meta-analysis of six trials showed that re-operation was more common after TUIP (18.4%) than after M-TURP (7.2%) [331]. Tolerability and safety: An RCT comparing conventional TUIP vs. TUIP using holmium laser reported both procedures to be safe with low complication rates; however, the operation time and retrograde ejaculation rate was significantly lower in the conventional TUIP arm [330]. No cases of TUR-syndrome have been recorded after TUIP. The risk of bleeding after TUIP is small [331]. Practical considerations: Transurethral incision of the prostate is an effective treatment for moderate-to-severe LUTS secondary to BPO. The choice between M-TURP and TUIP should be based primarily on prostate volume (30 mL TUIP) [331]. Summary of evidence Transurethral incision of the prostate shows similar efficacy and safety to M-TURP for treating moderate-to-severe LUTS secondary to BPO in men with prostates < 30 mL. No case of TUR-syndrome has been recorded, the risk of bleeding requiring transfusion is negligible and retrograde ejaculation rate is significantly lower after TUIP, but the re-operation rate is higher compared to M-TURP. The choice between TUIP and TURP should be based primarily on prostate volume (< 30 mL and 30-80 mL suitable for TUIP and TURP, respectively).

Recommendation Offer transurethral incision of the prostate to surgically treat moderate-to-severe LUTS in men with prostate size < 30 mL, without a middle lobe.

LE 1a 1a

4

Strength rating Strong

5.3.2 Enucleation of the prostate 5.3.2.1 Open prostatectomy Mechanism of action: Open prostatectomy is the oldest surgical treatment for moderate-to-severe LUTS secondary to BPO. Obstructive adenomas are enucleated using the index finger, approaching from within the bladder (Freyer procedure) or through the anterior prostatic capsule (Millin procedure). It is used for substantially enlarged glands (> 80-100 mL). Efficacy: Open prostatectomy reduces LUTS by 63-86% (12.5-23.3 IPSS points), improves QoL score by 60-87%, increases mean Qmax by up to 375% (+16.5-20.2 mL/s), and reduces PVR by 86-98%. Efficacy is maintained for up to six years [332-337]. Data from an Austrian nationwide study of 1,286 men submitted to OP showed that the endourological re-intervention rates after primary OP were 0.9%, 3.0%, 6.0%, and 8.8%, at three months, one year, five years, and eight years, respectively. The respective incidence of re-TURP was 0.5%, 1.8%, 3.7% and 4.3%, respectively [9]. Two meta-analyses [338, 339] evaluated the overall efficacy of OP performed via a transvesical approach vs. two transurethral enucleation techniques for treating patients with large glands, namely bipolar transurethral enucleation of the prostate (B-TUEP) and holmium laser enucleation of the prostate (HoLEP). The larger study included nine RCTs involving 758 patients [339]. Five RCTs compared OP with B-TUEP [337, 340-343] and four RCTs compared OP with HoLEP [332, 333, 344, 345]. At three, six, twelve and 24-months follow-up there were no significant differences in Qmax [339]. Post-void residual, PSA, IPSS and QoL score showed no significant differences at one, three, six and twelve months follow-up [339]. Randomised controlled trials indicate that OP is as effective as HoLEP for improving micturition in large prostates [332, 333], with similar improvement regarding Qmax, IPSS score and re-operation rates after five years [332].

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Tolerability and safety: Open prostatectomy mortality has decreased significantly during the past two decades (< 0.25%) [336]. Data from an Austrian nationwide study totalling 1,286 men submitted to OP showed mortality rates of 0.2% at 30 days and 0.4% at 90 days [293]. The estimated transfusion rate is about 7-14% [332, 335, 336, 338]. Long-term complications include transient urinary incontinence (up to 10%), BNC and urethral stricture (about 6%) [332-334, 338, 346]. Two meta-analyses evaluated the overall safety of OP performed via a transvesical approach vs. B-TUEP and HoLEP [338, 339]. Operation time did not differ significantly between OP and B-TUEP, but was significantly shorter for OP compared to HoLEP. Catheterisation and hospitalisation time were significantly longer for OP, which was also associated with more blood transfusions. There were no significant differences regarding other complications. There was no significant difference in IIEF-5 at three, six, twelve and 24-months follow-up. Practical considerations: Open prostatectomy is the most invasive surgical method, but it is an effective and durable procedure for the treatment of LUTS/BPO. In the absence of an endourological armamentarium including a holmium laser or a bipolar system and with appropriate patient consent, OP is a reasonable surgical treatment of choice for men with prostates > 80 mL. Summary of evidence Open prostatectomy is an effective and durable procedure for the treatment of LUTS/BPO, but it is the most invasive surgical method. Open prostatectomy shows similar short- and mid-term efficacy to B-TUEP and HoLEP for treating moderate-to-severe LUTS secondary to BPO in patients with large prostates. Open prostatectomy has a less favourable peri-operative safety profile compared to B-TUEP and HoLEP. The long-term functional results of OP are comparable to HoLEP.

LE 1b 1a 1a 1b

Recommendation Strength rating Offer open prostatectomy in the absence of bipolar transurethral enucleation of the prostate Strong and holmium laser enucleation of the prostate to treat moderate-to-severe LUTS in men with prostate size > 80 mL. 5.3.2.2 Bipolar transurethral enucleation of the prostate (B-TUEP) Mechanism of action: Following the principles of bipolar technology (section 5.3.1.1), the obstructive adenoma is enucleated endoscopically by the transurethral approach. Bipolar transurethral enucleation evolved from plasmakinetic (PK) B-TURP and was introduced by Gyrus ACMI. The technique, also referred to as PK enucleation of the prostate (PKEP), utilises a bipolar high-frequency generator and a variety of detaching instruments, for this true bipolar system, including a point source in the form of a axipolar cystoscope electrode suitable for enucleation [347] or a resectoscope tip/resection loop [348, 349]. More recently, a novel form of B-TUEP has been described, bipolar plasma enucleation of the prostate (BPEP), stemming from B-TURP (TURis, Olympus Medical), that utilises a bipolar high frequency generator and a variety of detaching instruments including a mushroom- or button-like vapo-electrode [343, 350] and a Plasmasect enucleation electrode [351] for this quasi-bipolar system. Bipolar transurethral enucleation of the prostate is followed by either morcellation [343, 347] or resection [348-350, 352-354] of the enucleated adenoma. Efficacy: One RCT evaluating PKEP vs. M-TURP in 204 patients with mean prostate volume < 80 mL reported a significant improvement in IPSS, QoL, and Qmax, with urodynamically proven de-obstruction favouring PKEP at 36 months follow-up [349]. The RCT concluded that the mid-term clinical efficacy of PKEP was comparable to M-TURP [349]. A meta-analysis evaluating data from five RCTs including 666 patients submitted to B-TUEP (PKEP or BPEP) vs. B-TURP, reported similar efficacy at twelve months in terms of IPSS, QoL and Qmax [355]. Two RCTs evaluated the mid-term efficacy of PKEP vs. B-TURP at 36 months [348, 353] and one RCT evaluated long-term efficacy at 60 months [354]. Efficacy was significantly better for PKEP in patients with large prostates at 36, 48 and 60 months [348, 354]. Comparative data on efficacy for B-TUEP vs. OP and the various forms of laser enucleation are presented in section 5.3.2.1 to 5.3.2.5, respectively. Tolerability and safety: An RCT evaluating PKEP vs. M-TURP in patients with mean prostate volume < 80 mL and 36 month follow-up reported that PKEP is superior to M-TURP in terms of haemoglobin drop, irrigation, catheterisation and hospitalisation time [349]. No significant differences between the arms were reported in operation time, blood transfusion rates, sexual function or any other reported complications (TUR-syndrome, clot retention, incontinence, retrograde ejaculation, urethral structures/BNC) [349]. A meta-analysis including

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five RCTs evaluating B-TUEP vs. B-TURP reported: similar operation, catheterisation and hospitalisation times; lower acute urine retention rates; significantly reduced haemoglobin drop and blood transfusion rates; no difference in erectile function; and no difference in all other reported complication rates including urethral stricture/BNC rates for B-TUEP at 24 months follow-up [355]. No difference in urethral stricture/BNC rates was reported at 60 months follow-up [354]. Comparative data on efficacy for B-TUEP vs. OP and the various forms of laser enucleation are presented in section 5.3.2.1 to 5.3.2.5, respectively. Summary of evidence Bipolar transurethral (plasmakinetic) enucleation of the prostate shows favourable mid- to long-term efficacy compared to TURP. Bipolar transurethral (plasmakinetic) enucleation of the prostate has a favourable peri-operative safety profile and demonstrates similar mid- to long-term safety compared to TURP. Recommendation Offer bipolar transurethral (plasmakinetic) enucleation of the prostate to men with moderate-to-severe LUTS as an alternative to transurethral resection of the prostate.

LE 1b 1b

Strength rating Weak

5.3.2.3 Holmium laser enucleation of the prostate Mechanism of action: The holmium:yttrium-aluminium garnet (Ho:YAG) laser (wavelength 2,140 nm) is a pulsed solid-state laser that is absorbed by water and water-containing tissues. Tissue coagulation and necrosis are limited to 3-4 mm, which is enough to obtain adequate haemostasis [356]. Efficacy: An initial meta-analysis reported no significant differences in short-term efficacy (Qmax) and re-intervention rates (4.3% vs. 8.8%) between HoLEP and M-TURP [357]; however, subsequent meta-analyses reported favourable short-term efficacy (Qmax and IPSS) for HoLEP [289, 320, 355, 358]. Two meta-analyses evaluating HoLEP vs. B-TURP showed no significant differences in short-term efficacy (IPSS, QoL score and Qmax) [355, 359]. One RCT comparing HoLEP with M-TURP in a small number of patients with mean prostate volume < 80 mL and a seven year follow-up found that the functional long term results were comparable [360]. Another RCT comparing HoLEP with B-TURP in patients with prostate volume < 80 mL reported no significant difference in IPSS, QoL score and Qmax at 24 months [361]. Long-term (72 months) improvement in IPSS and Qmax was better for HoLEP, but there were no clinically relevant differences between the arms [362]. Comparative efficacy data for HoLEP vs. OP is presented in section 5.3.2.1. One small RCT evaluating HoLEP vs. PKEP in patients with mean prostate volume < 80 mL reported similar improvements in IPSS and Qmax as well as similar re-operation rates at twelve months follow-up [347]. Tolerability and safety: Meta-analyses found that HoLEP has longer operation times, shorter catheterisation and hospitalisation times, reduced blood loss, fewer blood transfusions and no significant differences in urethral strictures (2.6% vs. 4.4%) and stress urinary incontinence (1.5% vs. 1.5%) rates compared to M-TURP [320, 355, 357, 358, 363]. Two meta-analyses evaluated HoLEP vs. B-TURP [355, 359]. Zhang et al., reported longer operation times for HoLEP, but no significant differences in hospitalisation time or complication rates whilst Qian et al., reported no significant differences in operation and catheterisation times or short-term complication rates [355, 359]. A RCT comparing HoLEP with B-TURP in patients with prostate volume < 80 mL reported longer operation time, shorter catheterisation and hospitalisation times and a lower risk for haemorrhage for HoLEP with no significant differences in blood transfusion rates or other complication rates at 24 months [361]. Comparative data on safety of HoLEP vs. OP are presented in section 5.3.2.1. One small RCT evaluating HoLEP vs. PKEP in patients with mean prostate volume < 80 mL reported significantly shorter operation times for HoLEP, but similar catheterisation and hospitalisation times and complication rates at twelve months follow-up [347]. Holmium laser enucleation of the prostate has been safely performed in patients using anticoagulant and/or antiplatelet medications [364, 365]. However, current limitations include: a lack of RCTs; limited data on short- and mid-term complications and bridging therapy; data presentation does not allow for separate interpretation of either of the two substantially different topics of antiplatelet and anticoagulant therapy. The impact on erectile function and retrograde ejaculation is comparable between HoLEP and TURP [366, 367]. Erectile function did not decrease from baseline in either group; three quarters of sexually active patients had retrograde ejaculation after HoLEP. Data have shown that ejaculation and orgasm perception are the two most impacted domains after HoLEP [368]. Attempts to maintain ejaculatory function with HoLEP have been reported to be successful in up to 46.2% of patients [369].

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Practical considerations: Holmium laser enucleation of the prostate requires experience and relevant endoscopic skills. The experience of the surgeon is the most important factor affecting the overall occurrence of complications [370, 371]. Mentorship programmes are advised to improve surgical performance from both an institutional and personal learning curve perspective [372-374]. Summary of evidence Laser enucleation of the prostate using Ho:YAG laser (HoLEP) demonstrates similar mid- to long-term efficacy when compared to TURP. Laser enucleation of the prostate using Ho:YAG laser (HoLEP) demonstrates similar short-term safety when compared to TURP. Laser enucleation of the prostate using Ho:YAG laser (HoLEP) demonstrates longer operation times, but a more favourable peri-operative profile when compared to TURP. Recommendation Offer laser enucleation of the prostate using Ho:YAG laser (HoLEP) to men with moderateto-severe LUTS as an alternative to transurethral resection of the prostate or open prostatectomy.

LE 1b 1a 1a

Strength rating Strong

5.3.2.4 Thulium:yttrium-aluminium-garnet laser (Tm:YAG) enucleation of the prostate Mechanism of action: The Tm:YAG laser has been described in section 5.3.1.3. Enucleation using the Tm:YAG laser includes ThuVEP (vapoenucleation i.e. excising technique) and ThuLEP (blunt enucleation). Efficacy: A meta-analysis evaluating ThuLEP vs. M-TURP and B-TURP reported no clinically relevant differences in Qmax, IPSS and QoL score [355]. An RCT with five years follow-up comparing ThuLEP with B-TURP found no difference between the two procedures for Qmax, IPSS, PVR, and QoL [375]. A meta-analysis [376] evaluating ThuLEP vs. HoLEP showed no clinically relevant differences in IPSS, QoL score and Qmax at twelve months in accordance with one RCT showing similar results at eighteen months [377]. Furthermore, ThuLEP and PKEP were compared in one RCT with twelve months follow-up the outcome of which showed no difference with regard to efficacy [378]. There are mainly prospective case studies on ThuVEP showing a significant improvement in IPSS, Qmax, and PVR after treatment [379-382]. Tolerability and safety: A meta-analysis evaluating ThuLEP vs. M-TURP and B-TURP reported a longer operation time and a shorter hospitalisation time for ThuLEP compared to M-TURP and B-TURP, respectively with no difference in complication rates [355]. A meta-analysis [376] evaluating ThuLEP vs. HoLEP showed a significant difference is enucleation time favouring ThuLEP, but no significant differences in operation, catheterisation and hospitalisation times short-term complication rates, in accordance with one RCT showing similar results, including no urethral and bladder neck strictures, at eighteen months [377]. ThuLEP and PKEP were compared in one RCT with twelve months follow-up [378]. No significant difference in complication rates was detected, but haemoglobin level decrease and catheterisation time was significantly lower for ThuLEP. In comparative studies ThuVEP show high intra-operative safety [383], as well as in case series in patients with large prostates [379] and anticoagulation or bleeding disorders [380, 384]. A study focusing on post-operative complications after ThuVEP reported adverse events in 31% of cases, with 6.6% complications greater then Clavien grade 2 [385]. One case control study on ThuVEP with 48-month follow-up reported longterm durability of voiding improvements and overall re-operation rates of 2.4% [384]. Two studies addressed the impact of ThuVEP on sexual function, demonstrating no effect on erectile function with increased prevalence of retrograde ejaculation post-operatively [386, 387]. Practical considerations: ThuLEP seems to offer similar efficacy and safety when compared to TURP, bipolar enucleation and HoLEP; whereas, ThuVEP is not supported by RCTs. Based on the limited number of RCTs and lack of long-term follow-up data there is a need for ongoing investigation of these techniques. Summary of evidence LE 1b Enucleation of the prostate using the Tm:YAG laser demonstrates similar efficacy when compared to M-TURP/bipolar transurethral (plasmakinetic) enucleation, HoLEP and B-TURP in the short-, mid-, and long-term, respectively. 1b Enucleation of the prostate using the Tm:YAG laser (ThuLEP) demonstrates similar safety compared to TURP/bipolar transurethral (plasmakinetic) enucleation, and HoLEP in the short- and mid-term, respectively.

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MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021

Vapoenucleation of the prostate using a Tm:YAG laser (ThuVEP) seems to be safe in patients with large prostates and those receiving anticoagulant or antiplatelet therapy. Recommendations Offer enucleation of the prostate using the Tm:YAG laser (ThuLEP, ThuVEP) to men with moderate-to-severe LUTS as an alternative to transurethral resection of the prostate, holmium laser enucleation or bipolar transurethral (plasmakinetic) enucleation. Offer Tm:YAG laser enucleation of the prostate to patients receiving anticoagulant or antiplatelet therapy.

2b

Strength rating Weak

Weak

5.3.2.5 Diode laser enucleation of the prostate Mechanism of action: For prostate surgery, diode lasers with a wavelength of 940, 980, 1,318, and 1,470 nm (depending on the semiconductor used) are marketed for vaporisation and enucleation. Only a few have been evaluated in clinical trials [385]. Efficacy: One small RCT comparing 1,318 nm diode laser enucleation of the prostate (DiLEP) with B-TURP in patients with mean prostate volume < 80 mL reported no significant differences in IPSS, QoL score, Qmax and PVR at six months follow-up [388]. Another RCT comparing 1,470 nm DiLEP with B-TURP in 157 patients with mean prostate volume < 80 mL also reported no significant differences in IPSS, QoL score, Qmax and PVR at twelve months follow-up [389]. In addition, three RCTs comparing 980 nm DiLEP with PKEP in patients with mean prostate volume < 80 mL [390, 391] and > 80 mL [392] reported no significant differences in IPSS, QoL score, Qmax and PVR at twelve months follow-up. Tolerability and safety: One small RCT comparing 1,318 nm DiLEP with B-TURP in patients with mean prostate volume < 80 mL and six months follow-up reported a significantly longer operation time for DiLEP, but shorter catheterisation and hospitalisation times, as well as less blood loss (without differences in blood transfusion rates) [388]. No differences in complication rates were reported between the two arms [388]. Another RCT comparing 1,470 nm DiLEP with B-TURP in 157 patients with mean prostate volume < 80 mL and twelve months follow-up reported significantly shorter operation, catheterisation and hospitalisation times with less blood loss (without differences in blood transfusion rates) for DiLEP, with no differences in complication rates between the two arms [389]. Three RCTs comparing 980 nm DiLEP with PKEP in patients with mean prostate volume < 80 mL [390, 391] and > 80 mL [392] and twelve months follow-up reported conflicting peri-operative outcomes: operation time (no difference between arms [390], significanly shorter for DiLEP [391] or sgnificanly longer for DiLEP [392]); catheterisation time (no difference between the two arms [390], significanly shorter for DiLEP [391, 392]); hospitalisation time (no difference between arms [390, 391], significanly shorter for DiLEP [392]); blood loss (no difference in haemoglobin drop between arms [390], significantly lower haemoglobin drop for DiLEP [391, 392]). All trials reported no differences in blood transfusion rates and complication rates [390392]. Practical considerations: Diode laser enucleation seems to offer similar efficacy and safety when compared to either B-TURP or bipolar transurethral (plasmakinetic) enucleation. Based on the limited number, mainly low-quality RCTs, and controversial data on the retreatment rate, results for diode laser enucleation should be evaluated in further higher quality RCTs. Summary of evidence Laser enucleation of the prostate using the 1,318 nm or 1,470 laser showed comparable short-term efficacy and safety to B-TURP. Peri-operative parameters like blood loss, catheterisation time and hospital stay are in favour of diode enucleation. Laser enucleation of the prostate using the 980 nm laser showed comparable short-term efficacy and safety to bipolar transurethral (plasmakinetic) enucleation. Recommendation Offer 120-W 980 nm, 1,318 nm or 1,470 nm diode laser enucleation of the prostate to men with moderate-to-severe LUTS as a comparable alternative to bipolar transurethral (plasmakinetic) enucleation or bipolar transurethral resection of the prostate.

LE 1b

1b

Strength rating Weak

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5.3.2.6 Enucleation techniques under investigation 5.3.2.6.1 Minimal invasive simple prostatectomy Mechanism of action: The term minimal invasive simple prostatectomy (MISP) includes laparoscopic simple prostatectomy (LSP) and robot-assisted simple prostatectomy (RASP). The technique for LSP was first described in 2002 [393], while the first RASP was reported in 2008 [394]. Both LSP and RASP are performed using different personalised techniques, based on the transcapsular (Millin) or transvesical (Freyer) techniques of OP. An extraperitoneal approach is mostly used for LSP, while a transperitoneal approach is mostly used for RASP. Efficacy: A SR and meta-analysis showed that in 27 observational studies including 764 patients, the mean increase in Qmax was 14.3 mL/s, and the mean improvement in IPSS was 17.2 [395]. Mean duration of operation was 141 minutes and the mean intra-operative blood loss was 284 mL. One hundred and four patients (13.6%) developed a surgical complication. In comparative studies to OP, length of hospital stay, length of catheter use and estimated blood loss were significantly lower in the MISP group, while the duration of operation was longer than in OP. There were no differences in improvements in Qmax, IPSS and perioperative complications between both procedures. Two recent retrospective series on RASP were not included in the meta-analysis which confirm these findings [396, 397]. The largest retrospective series reports 1,330 consecutive cases including 487 robotic (36.6%) and 843 laparoscopic (63.4%) simple prostatectomy cases. The authors confirm that both techniques can be safely and effectively done in selected centres [396]. Tolerability and safety: In the largest series, the post-operative complication rate was 10.6% (7.1% for LSP and 16.6% for RASP), most of the complications being of low grade. The most common complications in the RASP series were haematuria requiring irrigation, UTI and AUR; in the LSP series, the most common complications were UTI, ileus and AUR. In the most recent, largest comparative analysis of robotic vs. OP for large-volume prostates, a propensity score-matched analysis was performed with five covariates. Robotic compared with OP demonstrated a significant shorter average length of hospital stay, but longer mean operative time. The robotic approach was also associated with a lower estimated blood loss. Improvements in maximal flow rate, IPSS, QoL, PVR and post-operative PSA levels were similar before and after surgery for both groups. There was no difference in complications between the groups [398]. Practical considerations: Minimal invasive simple prostatectomy seems comparable to OP in terms of efficacy and safety, providing similar improvements in Qmax and IPSS [395]. However, most studies are of a retrospective nature. High-quality studies are needed to compare the efficacy, safety, and hospitalisation times of MISP and both OP and endoscopic methods. Long-term outcomes, learning curve and cost of MISP should also be evaluated. Summary of evidence LE Minimal invasive simple prostatectomy is feasible in men with prostate sizes > 80 mL needing surgical 1a treatment; however, RCTs are needed.

5.3.2.6.2 532 nm (‘Greenlight’) laser enucleation of the prostate Mechanism of action: The Potassium-Titanyl-Phosphate (KTP) and the lithium triborate (LBO) lasers work at a wavelength of 532 nm. Laser energy is absorbed by haemoglobin, but not by water. Vaporisation leads to immediate removal of prostatic tissue. Three “Greenlight” lasers exist, which differ not only in maximum power output, but more significantly in fibre design and the associated energy tissue interaction of each. The standard Greenlight device today is the 180-W XPS laser, but the majority of evidence is published with the former 80-W KTP or 120-W HPS (LBO) laser systems. Two approaches for KTP/LBO laser based enucleation technique exist [399]. GreenLEP is an anatomical enucleation technique following the principle of blunt dissection of the adenoma with the sheath and laser energy for incision as described for ThuLEP [400]. En bloc GreenLEP preparation has been popularised with the same approach. A variation of the most commonly applied GreenLEP technique, with tissue morcellation, is the in situ vaporisation of apically enucleated tissue, also referred to as anatomic vaporisation-incision technique [400, 401]. Lithium triborate/Greenlight vapoenucleation on the other hand uses vapoincising laser energy to cut out the tissue [402]. To date no RCTs evaluating enucleation using the KTP/ LBO laser exist [403].

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5.3.3 Vaporisation of the prostate 5.3.3.1 Bipolar transurethral vaporisation of the prostate Mechanism of action: Bipolar transurethral vaporisation of the prostate (B-TUVP) was introduced in the late 1990s (“PK” B-TUVP). The technique was derived from PK B-TURP and utilised a bipolar electrode and a highfrequency generator to create a plasma effect able to vaporise prostatic tissue [404]. With minimal direct tissue contact (near-contact; hovering technique) and heat production the bipolar electrode produces a constant plasma field (thin layer of highly ionized particles; plasma corona), allowing it to glide over the tissue and vaporise a limited layer of prostate cells without affecting the underlying tissue whilst achieving haemostasis, leaving behind a TURP-like cavity [405]. A distinct difference between B-TUVP and its ancestor (monopolar TUVP), is that B-TUVP displays thinner (< 2 mm) coagulation zones [406], compared to the disproportionate extent of those created by the former (up to 10 mm) [407], that potentially lead to mostly irritative side-effects and stress urinary incontinence [406, 408, 409]. Efficacy: Bipolar-TUVP has been evaluated as a TURP alternative for treating moderate-to-severe LUTS in thirteen RCTs to date, including a total of 1,244 men with a prostate size of < 80 mL [303, 410-421]. Early RCTs evaluated the PK B-TUVP system [410-414]; however, during the last decade, only the “plasma” B-TUVP system with the “mushroom- or button-like” electrode (Olympus, Medical) has been evaluated [303, 415-421]. Results have been pooled in three RCT-based meta-analyses [289, 422, 423], and a narrative synthesis has been produced in two SRs [289, 424]. The follow-up in most RCTs is twelve months [410-413, 415-417, 419, 421]. The longest follow-up is 36 months in a small RCT (n = 40) and eighteen months in a subsequent RCT n = 340); evaluating PK [414] and plasma B-TUVP [303], respectively. Early pooled results concluded that no significant differences exist in short-term efficacy (IPSS, QoL score, Qmax and PVR) between PK B-TUVP and TURP [289]. However, the promising initial efficacy profile of the former may be compromised by inferior clinical outcomes (IPSS, Qmax) at mid-term. Larger RCTs with longer follow-up are necessary to draw definite conclusions [289, 414]. A SR of seven RCTs comparing PK and plasma B-TUVP with TURP concluded that functional outcomes of B-TUVP and TURP do not differ [424]. The poor quality of the included RCTs and the fact that most data was derived from a single institution was highlighted [424]. A similar SR of eight RCTs comparing both B-TUVP techniques with TURP concluded that not enough consistent data suitable for a meta-analysis exists; that main functional results are contradictory; and that heterogeneity of RCTs, non-standardised techniques and methodological limitations do not permit firm conclusions [289]. A meta-analysis of six RCTs specifically evaluating plasma B-TUVP vs. TURP, concluded that both techniques result in a similar improvement of LUTS [423]. Tolerability and safety: Early pooled results concluded that no statistically significant differences exist collectively for intra-operative and short-term complications between PK B-TUVP and TURP, but peri-operative complications are significantly fewer after B-TUVP [289]. However, the results of a statistical analysis comparing pooled specific complication rates were not directly reported in this meta-analysis [289]. Mid-term safety results (urethral stricture, ED, and retrograde ejaculation) have also been reported to be similar [414], but larger RCTs with longer follow-up are necessary to draw definite conclusions [289, 414]. A SR of seven RCTs comparing PK and plasma B-TUVP with TURP concluded that most RCTs suggest a better haemostatic efficiency for B-TUVP, resulting in shorter catheterisation (42.5 vs. 77.5 hours) and hospitalisation times (3.1 vs. 4.4 days) [424]. A similar SR of eight RCTs comparing both B-TUVP techniques with TURP concluded that not enough consistent data suitable for a meta-analysis exists and that heterogeneity of RCTs, non-standardised techniques and methodological limitations do not permit firm conclusions [289]. A meta-analysis of six RCTs specifically evaluating plasma B-TUVP vs. TURP, concluded that no significant differences exist between the techniques in overall complication and transfusion rates [423]. However, a statistically significant difference was detected collectively in major complication rates (Clavien 3, 4; including urethral stricture, severe bleeding necessitating re-operation and urinary incontinence) and in the duration of catheterisation favouring plasma B-TUVP. Practical considerations: Bipolar-TUVP and TURP have similar short-term efficacy. Plasmakinetic B-TUVP has a favourable peri-operative profile, similar mid-term safety, but inferior mid-term efficacy compared to TURP. Plasma B-TUVP has a lower short-term major morbidity compared to TURP. Randomised controlled trials of higher quality, multicentre RCTs, and longer follow-up periods are needed to evaluate B-TUVP in comparison to TURP. Summary of evidence Bipolar-TUVP and TURP have similar short-term efficacy. Plasmakinetic B-TUVP has a favourable peri-operative profile, similar mid-term safety, but inferior mid-term efficacy compared to TURP. Plasma B-TUVP has a lower short-term major morbidity rate compared to TURP.

MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021

LE 1a 1a 1a

37

Recommendation Offer bipolar transurethral vaporisation of the prostate as an alternative to monopolar transurethral resection of the prostate to surgically treat moderate-to-severe LUTS in men with a prostate volume of 30-80 mL.

Strength rating Weak

5.3.3.2 532 nm (‘Greenlight’) laser vaporisation of the prostate Mechanism of action: The Potassium-Titanyl-Phosphate (KTP) and the lithium triborate (LBO) lasers have been described in section 5.3.2.6.2. Efficacy: A meta-analysis of the nine available RCTs comparing photoselective vaporisation of the prostate (PVP) using the 80-W and 120-W lasers with TURP was performed in 2012 [425]. No differences were found in Qmax and IPSS between 80-W PVP and TURP, but only three RCTs provided sufficient twelve month data to be included in the meta-analysis [426-428]. Another meta-analysis from 2016, of four RCTs including 559 patients, on the 120-W laser, demonstrated no significant difference in functional and symptomatic parameters at 6-, 12-, and 24-month follow-up when compared to TURP [429]. The only available RCT for the 180-W laser reported non-inferiority to TURP in terms of IPSS, Qmax, PVR volume, prostate volume reduction, PSA decrease and QoL questionnaires. Efficacy outcomes were similar to TURP with stable results at 24 months follow-up [430]. The longest RCT comparing the 120-W HPS laser with TURP had a follow-up of 36 months and showed a comparable improvement in IPSS, Qmax, and PVR [431]. Comparable improvements in IPSS, QoL, Qmax, or urodynamic parameters were reported from two RCTs with a maximum follow-up of 24 months [427, 432]. A SR and meta-analysis of eleven RCTs comparing M-TURP with the 80-W KTP or 120-W HPS system found no significant difference with respect to IPSS and Qmax improvement [433]. One RCT comparing HoLEP to PVP, in patients with prostates > 60 mL, showed comparable symptom improvement, but significantly higher flow rates and lower PVR volume after HoLEP at short-term follow-up; in addition, PVP showed a 22% conversion rate to TURP [434]. Tolerability and safety: A meta-analysis of RCTs comparing the 80-W and 120-W lasers with TURP showed a significantly longer operating time, but shorter catheterisation time and length of hospital stay after PVP [289]. Blood transfusions and clot retention were less with PVP. No difference was noted in post-operative urinary retention, infection, meatal stenosis, urethral stricture, or bladder neck stenosis [289]. In a meta-analysis including trials with the 120-W laser, patients in the PVP group demonstrated significantly lower transfusion rates, shorter catheterisation time and shorter duration of hospital stay compared to TURP. Re-operation rates and operation time were in favour of TURP. No significant differences were demonstrated for treatment for urethral stricture, BNC, incidence of incontinence and infection [429]. A SR and meta-analysis of eleven RCTs comparing M-TURP with the 80-W KTP or 120-W HPS system found that PVP was superior to M-TURP with regard to transfusion rate, clot retention, catheterisation and hospitalisation time [433]. 180-W Greenlight laser prostatectomy is non-inferior to TURP in terms of peri-operative complications. Re-operation free survival during 24 months follow-up was comparable between the TURP-arm and the 180-W XPS laser-arm [430]. In an RCT comparing the 120-W HPS laser with TURP, with a follow-up of 36 months, the re-operation rate was significantly higher after PVP (11% vs. 1.8%; p = 0.04) [431]. Based mostly on case series the 80-,120- and 180-W Greenlight laser appears to be safe in high-risk patients undergoing anticoagulation treatment [435-438]; however, patients under anticoagulation therapy were either excluded from or represented a very small sample in currently available RCTs. In one study, anticoagulant patients had significantly higher rates of bladder irrigation (17.2%) compared with those not taking anticoagulants (5.4%) [438]. In contrast, another retrospective study focusing on the 180-W LBO laser did not find any significant differences between patients receiving or not receiving anticoagulants [439]. A retrospective study of a mixed cohort of patients, treated with 80-W KTP PVP and 120-W LBO HPS, revealed that delayed gross haematuria was common in patients (33.8%) during an average follow-up of 33 months [440]. A retrospective review of a database of patients undergoing 180-W PVP, without interruption of anticoagulation therapy, had a 30.5% rate of peri-operative adverse events with a significant occurrence of high grade Clavien Dindo events [441]. Safety in patients with urinary retention, impaired detrusor contractility, elderly patients or prostates > 80 mL was shown in various prospective short-term non-randomised trials. No RCT including prostates > 100 mL has been reported; therefore, comparison of retreatment rates between prostate volumes of different sizes is not possible [442-444]. An RCT with twelve months follow-up reported a retrograde ejaculation rate of 49.9% following PVP with an 80-W laser vs. 56.7% for TURP, there was no impact on erectile function in either arm of the trial [445]. Additional studies have also reported no difference between OP/TURP and Greenlight PVP for erectile function [446, 447]. However, IIEF-5 scores were significantly decreased at 6-, 12-, and 24- months in patients with preoperative IIEF-5 greater than 19 [448]. 38

MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021

Practical considerations: The 180-W XPS represents the current standard of generators for PVP; however, the number and quality of supporting publications are low, especially for large glands (> 100 mL), with no long-term follow up. Summary of evidence Laser vaporisation of the prostate using the 80-W KTP and the 120-W LBO laser (PVP) demonstrated higher intra-operative safety with regard to haemostatic properties when compared to TURP. Perioperative parameters such as catheterisation time and hospital stay are in favour of PVP, whereas operation time and risk of re-operation are in favour of TURP. Short-term results for the 80-W KTP laser and mid-term results for the 120-W LBO laser were comparable to TURP. Laser vaporisation of the prostate using the 180-W LBO laser (PVP) demonstrated higher intraoperative safety with regard to haemostatic properties when compared to TURP. Peri-operative parameters such as catheterisation time and hospital stay were in favour of PVP, whereas operation time was in favour of TURP. Short- to mid-term results are comparable to TURP. Laser vaporisation of the prostate using the 80-W KTP and 120-W LBO lasers seems to be safe for the treatment of patients receiving antiplatelet or anticoagulant therapy. Laser vaporisation of the prostate using the 180-W LBO laser seems to be safe for the treatment of patients receiving antiplatelet or anticoagulant therapy; however, the level of available evidence is low. Recommendations Offer 80-W 532-nm Potassium-Titanyl-Phosphate (KTP) laser vaporisation of the prostate to men with moderate-to-severe LUTS with a prostate volume of 30-80 mL as an alternative to transurethral resection of the prostate (TURP). Offer 120-W 532-nm Lithium Borat (LBO) laser vaporisation of the prostate to men with moderate-to-severe LUTS with a prostate volume of 30-80 mL as an alternative to TURP. Offer 180-W 532-nm LBO laser vaporisation of the prostate to men with moderate-tosevere LUTS with a prostate volume of 30-80 mL as an alternative to TURP. Offer laser vaporisation of the prostate using 80-W KTP, 120- or 180-W LBO lasers for the treatment of patients receiving antiplatelet or anticoagulant therapy with a prostate volume < 80 mL.

LE 1a

1b

2 3

Strength rating Strong

Strong Strong Weak

5.3.3.3 Vaporisation techniques under investigation 5.3.3.3.1 Diode laser vaporisation of the prostate Mechanism of action: For prostate surgery, diode lasers with a wavelength of 980 nm are marketed for vaporisation; however, only a few have been evaluated in clinical trials [317]. Efficacy: Two RCTs for 120-W 980 nm diode laser vaporisation vs. M-TURP are available [449, 450]. The first RCT with 24 month follow-up reported equal symptomatic and clinical parameters at one and six months. However, at 12- and 24-months the results were significantly in favour of TURP, repeat TURP was more frequent in the diode laser group [449]. The second RCT reported equivocal results for both interventions at 3-month follow-up [450]. Tolerability and safety: Published studies on 980 nm diode laser vaporisation indicate high haemostatic potential, although anticoagulants or platelet aggregation inhibitors were taken in 24% and 52% of patients, respectively [451, 452]. In a number of studies, a high rate of post-operative dysuria was reported [449, 451453]. In an RCT reflecting on peri-operative and post-operative complications no significant differences were demonstrated for clot retention, re-catheterisation, UUI and UTI [449]. Moreover, for late complications no significant differences could be demonstrated for re-operation rate, urethral stricture, bladder neck sclerosis, de novo sexual dysfunction and mean time of dysuria [449]. Fibre modifications can potentially reduce surgical time [454]. Early publications on diode vaporisation reported high re-operation rates (8-33%) and persisting stress urinary incontinence (9.1%) [449, 451-453]. Practical considerations: Diode laser vaporisation leads to similar improvements in clinical and symptomatic parameters during short-term follow-up and provides good haemostatic properties. Based on the limited number, mainly low quality RCTs, and controversial data on the retreatment rate, results for diode laser vaporisation should be evaluated in further higher quality RCTs.

MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021

39

Summary of evidence Laser vaporisation of the prostate using the 120-W 980 nm diode laser demonstrated high intraoperative safety with regard to haemostatic properties when compared to TURP. Peri-operative parameters like catheterisation time and hospital stay were in favour of diode lasers. Evidence is limited by the number and quality of the available studies. In a number of studies severe post-operative complications such as severe storage symptoms and persisting incontinence occurred with laser vaporisation of the prostate using the 120-W 980 nm diode laser. Laser vaporisation using the 120-W 980 nm diode laser seems to be safe with regard to haemostasis in patients receiving anticoagulant therapy.

LE 1b

3

3

5.3.4 Alternative ablative techniques 5.3.4.1 Aquablation – image guided robotic waterjet ablation: AquaBeam Mechanism of action: AquaBeam uses the principle of hydro-dissection to ablate prostatic parenchyma while sparing collagenous structures like blood vessels and the surgical capsule. A targeted high velocity saline stream ablates prostatic tissue without the generation of thermal energy under real-time transrectal ultrasound guidance; therefore, it is truly a robotic operation. After completion of ablation haemostasis is performed with a Foley balloon catheter on light traction or diathermy or low-powered laser, if necessary [455]. Efficacy: In a double-blind, multicentre, prospective RCT 181 patients were randomised to TURP or Aquablation [456, 457]. Mean total operative time was similar for Aquablation and TURP (33 vs. 36 minutes), but resection time was significantly lower for Aquablation (4 vs. 27 minutes). At six months patients treated with Aquablation and TURP experienced large IPSS improvements (-16.9 and -15.1, respectively). The study noninferiority hypothesis was satisfied. Larger prostates (50-80 mL) demonstrated a more pronounced benefit. At one year follow-up, mean IPSS reduction was 15.1 in the Aquablation group and 15.1 in the TURP group with a mean percent reduction in IPSS score of 67% in both groups. Ninety three percent and 86.7% of patients had improvements of at least five points from baseline, respectively. No significant difference in improvement of IPSS, QoL, Qmax and reduction of PVR was reported between the groups. One TURP subject (1.5%) and three Aquablation subjects (2.6%) underwent re-TURP within one year of the study procedure [458]. In the American cohort of this study (90 patients) one year data showed less anejaculation in patients treated with aquablation (9%) compared with TURP (45%) in sexually active subjects [457]. A subgroup analysis of the WATER study [456] reported that in men with larger more complex prostates Aquablation was associated with both superior symptom improvement and a better safety profile with less post-operative anejaculation [459]. In a cohort study of 101 men with a prostate volume between 80-150 mL mean IPSS improved from 23.2 at baseline to 5.9 at six months. Improvement in IPSS, QoL, Qmax and reduction of PVR were also significant at six months. No secondary procedures for tissue removal occurred as of the six months [460]. Another RCT comparing Aquablation with TURP performed urodynamic studies on 66 patients at six months follow-up and reported significant changes in pdetQmax (reductions of 35 and 34 cm H20, respectively) and large improvements in BOO Index in both groups [461]. Tolerability and safety: An RCT has shown that fewer men in the Aquablation group had a persistent ClavienDindo grade 1 or 2 or higher adverse event compared to TURP (26% vs. 42%) at three months following treatment. Among sexually active men the rate of anejaculation was lower in those treated with Aquablation compared to TURP (10% vs. 36%, respectively). There were no procedure-related adverse events after six months [458]. In patients with a prostate volume between 80-150 mL, bleeding related events were observed in fourteen patients (13.9%) of which eight (7.9%) occurred prior to discharge and six (5.9%) occurred within one month of discharge. Blood transfusions were required in eight (7.9%) patients, return to the theatre for fulguration in three (3.0%) patients, and both transfusion and fulguration in two patients (2.0%). Ejaculatory dysfunction occurred in 19% of sexually active men [460]. Practical considerations: During short-term follow-up, Aquablation provides non-inferior functional outcomes compared to TURP in patients with LUTS and a prostate volume between 30-80 mL. Longer term follow-up is necessary to assess the clinical value of Aquablation. Summary of evidence Aquablation appears to be as effective as TURP both subjectively and objectively; however, there are still some concerns about the best methods of achieving post-treatment haemostasis.

40

LE 1b

MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021

Recommendations Offer Aquablation* to patients with moderate-to-severe LUTS and a prostate volume of 30-80 mL as an alternative to TURP. Inform patients about the risk of bleeding and the lack of long-term follow-up data.

Strength rating Weak Strong

*Approach remains under investigation 5.3.4.2 Prostatic artery embolisation Mechanism of action: Prostatic artery embolisation (PAE) can be performed as a day case procedure under local anaesthesia with access through the femoral or radial arteries. Digital subtraction angiography displays arterial anatomy and the appropriate prostatic arterial supply is selectively embolised to effect stasis in treated prostatic vessels. Different techniques have been used for PAE. Atherosclerosis, excessive tortuosity of the arterial supply and the presence of adverse collaterals are anatomical obstacles for the technical approach. Cone beam computed tomography and contrast enhanced MR angiography can help identify prostatic arteries and prevent off-target embolisation particularly in patients with challenging anatomical configurations [462, 463]. Efficacy: Two RCTs were conducted for direct comparison of PAE with TURP [464, 465]. Both studies observed significant treatment outcomes for both procedures as compared to baseline values, but TURP was superior when considering urodynamic parameters such as Qmax and PVR. Improvement of LUTS as determined by IPSS and QoL was slightly more pronounced after TURP and reduction of prostate volume was significantly more efficient after TURP than PAE. Another RCT comparing PAE with TURP in 99 patients showed a mean reduction in IPSS from baseline to twelve weeks of −9.23 points after PAE and −10.77 points after TURP. At twelve weeks, PAE was less effective than TURP regarding improvements in Qmax (5.19 mL/s vs. 15.34 mL/s), PVR (−86.36 mL vs. −199.98 mL), prostate volume (−12.17 mL vs. −30.27 mL), and significant de-obstructive effectiveness according to pressure flow studies (56% vs. 93% shift towards less obstructive category). For secondary outcomes, compared with PAE, procedural time was shorter for TURP, but in PAE patients, bladder catheter indwelling time, and duration of hospital stay were significantly shorter [462]. Another SR and meta-analysis including the three above mentioned RCTs and two non-randomised comparative studies (n = 708 patients), showed that TURP achieved a significantly higher mean postoperative difference for IPSS and IPSS-QoL, 3.80 and 0.73 points, respectively compared to PAE [466]. All of the functional outcomes assessed were significantly superior after TURP: 3.62 mL/s for Qmax, 11.51 mL for prostate volume, 11.86 mL for PVR, and 1.02 ng/mL for PSA [466]. Tolerability and safety: In a SR of comparative studies PAE resulted in significantly more adverse events than TURP/OP (41.6% vs. 30.4%). The frequency of AUR after the procedures was significantly higher in the PAE group (9.4% vs. 2.0%) [467]. Another RCT however, reported fewer adverse events occurred after PAE than after TURP (36 vs. 70 events; p = 0.003). For secondary outcomes, PAE showed favourable results in terms of blood loss [462]. A SR and meta-analysis of four studies (506 patients) comparing PAE and TURP found no significant difference in the post-operative complication rate between TURP and PAE [468]. A SR of 708 patients whilst confirming that PAE was not as effective as TURP, it did report fewer side effects than established surgical procedures [466]. Post-operative erectile function measured by IIEF-5 was in favour of PAE with mean difference in change of 2.56 points. Concerns still exist about non-target embolisation, reported in earlier studies [469]; however, more recent studies report less incidents [466, 470]. Practical considerations: A multidisciplinary team approach of urologists and radiologists is mandatory and patient selection should be done by urologists and interventional radiologists together. The investigation of patients with LUTS to indicate suitability for invasive techniques should be performed by urologists only. This technically demanding procedure should only be done by an interventional radiologist with specific mentored training and expertise in PAE [471]. Patients with larger prostates (> 80 mL) may have the most to gain from PAE. The selection of LUTS patients who will benefit from PAE still needs to be better defined [466]. Further data with medium- and long-term follow-up are still required and comparison with other minimally invasive techniques would be valuable. However, current evidence of safety and efficacy of PAE appears adequate to support the use of this procedure for men with moderate-to-severe LUTS provided proper arrangements for consent and audit are in place; therefore, a recommendation has been given, but PAE remains under investigation.

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Summary of evidence Prostatic artery embolisation is less effective than TURP at improving symptoms and urodynamic parameters such as flow rate. Procedural time is longer for PAE compared to TURP, but blood loss, catheterisation and hospitalisation time are in favour of PAE. Recommendations Offer prostatic artery embolisation (PAE)* to men with moderate-to-severe LUTS who wish to consider minimally invasive treatment options and accept less optimal outcomes compared with transurethral resection of the prostate. Perform PAE only in units where the work up and follow-up is performed by urologists working collaboratively with trained interventional radiologists for the identification of PAE suitable patients. *Approach remains under investigation

LE 1a 1b

Strength rating Weak

Strong

5.3.4.3 Alternative ablative techniques under investigation 5.3.4.3.1 Convective water vapour energy (WAVE) ablation: The Rezum system Mechanism of action: The Rezum system uses radiofrequency power to create thermal energy in the form of water vapour, which in turn deposits the stored thermal energy when the steam phase shifts to liquid upon cell contact. The steam disperses through the tissue interstices and releases stored thermal energy onto prostatic tissue effecting cell necrosis. The procedure can be performed in an office based setting. Usually, one to three injections are needed for each lateral lobe and one to two injections may be delivered into the median lobe. Efficacy: In a multicentre, randomised, controlled study 197 men were enrolled and randomised in a 2:1 ratio to treatment with water vapour energy ablation or sham treatment [472]. At three months relief of symptoms, measured by a change in IPSS and Qmax were significantly improved and maintained compared to the sham arm, although only the active treatment arm was followed up to twelve months. No relevant impact was observed on PVR. Quality of life outcome was significantly improved with a meaningful treatment response of 52% at twelve months. Further validated objective outcome measures such as BPH impact index (BPHII), Overactive Bladder Questionnaire Short Form for OAB bother, and impact on QoL and International Continence Society Male Item Short Form Survey for male incontinence demonstrated significant amelioration of symptoms at three months follow-up with sustained efficacy throughout the study period of twelve months. The reported two year results in the Rezum cohort arm of the same study and the recently reported four year results confirmed durability of the positive clinical outcome after convective water vapour energy ablation [473, 474]. Surgical retreatment rate was 4.4% over four years [474]. Tolerability and safety: Safety profile was favourable with adverse events documented to be mild-to-moderate and resolving rapidly. Preservation of erectile and ejaculatory function after convective water vapour thermal therapy was demonstrated utilising validated outcome instruments such as IIEF and Male Sexual Health Questionnaire-Ejaculation Disorder Questionnaire [472]. Practical considerations: Randomised controlled trials against a reference technique are needed to confirm the first promising clinical results and to evaluate mid- and long-term efficacy and safety of water vapour energy treatment. 5.3.5 Non-ablative techniques 5.3.5.1 Prostatic urethral lift Mechanism of action: The prostatic urethral lift (PUL) represents a novel minimally invasive approach under local or general anaesthesia. Encroaching lateral lobes are compressed by small permanent suture-based implants delivered under cystoscopic guidance (Urolift®) resulting in an opening of the prostatic urethra leaving a continuous anterior channel through the prostatic fossa extending from the bladder neck to the verumontanum. Efficacy: In general, PUL achieves a significant improvement in IPSS (-39% to -52%), Qmax (+32% to +59%) and QoL (-48% to -53%) [475-480]. Prostatic urethral lift was initially evaluated vs. sham in a multicentre study with one [477] three [481] and five [482] years follow-up. The primary endpoint was met at three months with a 50% reduction in IPSS. In addition, Qmax increased significantly from 8.1 to 12.4 mL/s compared to baseline at three months and this result was confirmed at twelve months. The difference in clinical response for Qmax between both groups was of statistical significance. A relevant benefit with regard to PVR was not demonstrated compared to baseline or sham. At three years, average improvements from baseline were significant for total IPSS, QoL, Qmax and individual IPSS symptoms. There was no de novo, sustained

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ejaculatory or erectile dysfunction events and all sexual function assessments showed average stability or improvement after PUL. Improvements in IPSS, QoL, BPHII and Qmax were durable throughout the five years with improvement rates of 36%, 50%, 52%, and 44%, respectively. The re-treatment rate was 13.6% over five years. Adverse events were mild to moderate and transient. Sexual function was stable over five years with no de novo, sustained erectile, or ejaculatory dysfunction. Another RCT of 80 patients was conducted in three European countries, comparing PUL to TURP. At twelve months, IPSS improvement was -11.4 for PUL and -15.4 for TURP. There was no retrograde ejaculation among PUL patients with 40% in the TURP patients. Surgical recovery was measured using a validated instrument and confirmed that recovery from PUL is more rapid and more extensive in the first three to six months [483]. However, TURP resulted in much greater improvements in Qmax after twelve months compared to PUL. At 24 months, significant improvements in IPSS, IPSS QoL, BPHII, and Qmax were observed in both arms. Change in IPSS and Qmax in the TURP arm were superior to the PUL arm [484]. Improvements in QoL and BPHII score were not statistically different between the study arms. Prostatic urethral lift resulted in superior quality of recovery and ejaculatory function preservation. Ejaculatory function and bother scores did not change significantly in either treatment arm. In a meta-analysis of retrospective and prospective trials, pooled estimates showed an overall improvement following PUL, including IPSS, Qmax, and QoL [480]. Sexual function was preserved with a small improvement estimated at twelve months. Tolerability and safety: The most common complications reported post-operatively included haematuria (16-63%), dysuria (25-58%), pelvic pain (5-17.9%), urgency (7.1-10%), transient incontinence (3.6-16%), and UTI (2.9-11%) [477, 480-482]. Most symptoms were mild-to-moderate in severity and resolved within two to four weeks after the procedure. Prostatic urethral lift seems to have no significant impact on sexual function. Evaluation of sexual function as measured by IIEF-5, Male Sexual Health Questionnaire-Ejaculatory Dysfunction, and Male Sexual Health Questionnaire-Bother in patients undergoing PUL showed that erectile and ejaculatory function were preserved [475-479]. Practical considerations: There are only limited data on treating patients with an obstructed/protruding middle lobe [485]. It appears that they can be effectively treated with a variation in the standard technique, but further data are needed [485]. The effectiveness in large prostate glands has not been shown yet. Long-term studies are needed to evaluate the duration of the effect in comparison to other techniques. Summary of evidence Prostatic urethral lift improves IPSS, Qmax and QoL; however, these improvements are inferior to TURP at 24 months. Prostatic urethral lift has a low incidence of sexual side effects. Patients should be informed that long-term effects including the risk of retreatment have not been evaluated. Recommendation Offer Prostatic urethral lift (Urolift®) to men with LUTS interested in preserving ejaculatory function, with prostates < 70 mL and no middle lobe.

LE 1b 1b 4

Strength rating Strong

5.3.5.2 Intra-prostatic injections Mechanism of action: Various substances have been injected directly into the prostate in order to improve LUTS, these include Botulinum toxin-A (BoNT-A), fexapotide triflutate (NX-1207) and PRX302. The primary mechanism of action of BoNT-A is through the inhibition of neurotransmitter release from cholinergic neurons [486]. The detailed mechanisms of action for the injectables NX-1207 and PRX302 are not completely understood, but experimental data associates apoptosis-induced atrophy of the prostate with both drugs [486]. Efficacy: Results from clinical trials have shown only modest clinical benefits, that do not seem to be superior to placebo, for BoNT-A [487, 488]. A recent SR and meta-analysis showed no differences in efficacy compared with placebo and concluded that there is no evidence of clinical benefits in medical practice [489]. The positive results from Phase II-studies have not be confirmed in Phase III-trials for PRX302 [490, 491]. NX-1207 was evaluated in two multicentre placebo controlled double-blind randomised parallel group trials including a total of 995 patients with a mean follow-up of 3.6 years, IPSS change from baseline was significantly higher and AUR rate was significantly reduced in the treatment arm. The authors concluded that NX-1207 is an effective transrectal injectable for long-term treatment for LUTS and that treated patients have reduced need for further intervention [492]. MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021

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Safety: Studies including safety assessments have reported only a few mild and self-limiting adverse events for all injectable drugs [486]. A recent SR and meta-analysis showed low incident rates of procedure-related adverse events [489]. Two multicentre placebo controlled double-blind randomised parallel group trials with long-term follow-up evaluating NX-1207 detected no significant safety differences between the study arms [492]. Practical considerations: Although experimental evidence for compounds such as BoNT-A and PRX302 were promising for their transition to clinical use positive results from Phase II-studies have not be confirmed in Phase III-trials. Randomised controlled trials against a reference technique are needed to confirm the first promising clinical results of NX-1207. Summary of evidence Results from clinical trials have shown no clinical benefits for BoNT-A compared to placebo for the management of LUTS due to BPO. Results from clinical trials have shown clinical benefits for NX-1207 compared to placebo for the management of LUTS due to BPO. Recommendation Do not offer intraprostatic Botulinum toxin-A injection treatment to patients with male LUTS.

LE 1a 1b

Strength rating Strong

5.3.5.3 Non-ablative techniques under investigation 5.3.5.3.1 (i)TIND Mechanism of action: The iTIND is a device designed to remodel the bladder neck and the prostatic urethra and is composed of three elongated struts and an anchoring leaflet, all made of nitinol. Under direct visualisation the iTIND is deployed inside the prostate in expanded configuration. The intended mode of action is to compress obstructive tissue by the expanded device, thereby exerting radial force leading to ischaemic necrosis in defined areas of interest. The iTIND is left in position for five days. The resulting incisions may be similar to a Turner Warwick incision. In an outpatient setting the device is removed by standard urethroscopy. Efficacy: A single-arm, prospective study of 32 patients with a follow-up of three years was conducted to evaluate feasibility and safety of the procedure [493]. The change from baseline in IPSS, QoL score and Qmax was significant at every follow-up time point [494]. Tolerability and safety: The device has been reported to be well tolerated by all patients. Four early complications (12.5%) were recorded, including one case of urinary retention (3.1%), one case of transient incontinence due to device displacement (3.1%), and two cases of infection (6.2%). No further complications were recorded during the 36-month follow-up period. Practical considerations: Randomised controlled trials comparing iTIND to a reference technique are ongoing.

5.4

Patient selection

The choice of treatment depends on the assessed findings of patient evaluation, ability of the treatment to change the findings, treatment preferences of the individual patient, and the expectations to be met in terms of speed of onset, efficacy, side effects, QoL, and disease progression. Behavioural modifications, with or without medical treatments, are usually the first choice of therapy. Figure 3 provides a flow chart illustrating treatment choice according to evidence-based medicine and patient profiles. Surgical treatment is usually required when patients have experienced recurrent or refractory urinary retention, overflow incontinence, recurrent UTIs, bladder stones or diverticula, treatment-resistant macroscopic haematuria due to BPH/BPE, or dilatation of the upper urinary tract due to BPO, with or without renal insufficiency (absolute operation indications, need for surgery). Additionally, surgery is usually needed when patients have not obtained adequate relief from LUTS or PVR using conservative or medical treatments (relative operation indications). The choice of surgical technique depends on prostate size, comorbidities of the patient, ability to have anaesthesia, patients’ preferences, willingness to accept surgery-associated specific side-effects, availability of the surgical armamentarium, and experience of the surgeon with these surgical techniques. An algorithm for surgical approaches according to evidence-based medicine and the patient’s profile is provided in Figure 4.

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Figure 3: Treatment algorithm of male LUTS using medical and/or conservative treatment options. Treatment decisions depend on results assessed during initial evaluation. Note that patients’ preferences may result in different treatment decisions.

Male LUTS (without indications for surgery)

Bothersome symptoms?

no

yes

Nocturnal polyuria predominant

no

no

Prostate volume > 40 mL?

no

Education + lifestyle advice with or without α1-blocker/PDE5I

no

Storage symptoms predominant?

yes

yes

yes

Long-term treatment?

yes Residual storage symptoms

Watchful waiting with or without education + lifestyle advice

Add muscarinic receptor antagonist/beta -3 agonist

Education + lifestyle advice with or without 5α-reductase inhibitor ± α1blocker/PDE5I

Education + lifestyle advice with or without muscarinic receptor antagonist/beta -3 agonist

Education + lifestyle advice with or without vasopressin analogue

PDE5I = phosphodiesterase type 5 inhibitors.

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Figure 4: Treatment algorithm of bothersome LUTS refractory to conservative/medical treatment or in cases of absolute operation indications. The flowchart is stratified by the patient’s ability to have anaesthesia, cardiovascular risk, and prostate size.

Male LUTS

with absolute indicaons for surgery or non-responders to medical treatment or those who do not want medical treatment but request acve treatment

High-risk paents?

no

yes

yes

< 30 mL

Prostate volume

Can stop ancoagulaon/ anplatelet therapy

yes

Can have surgery under anaesthesia?

no

no

> 80 mL

30 – 80 mL

TUIP (1) TURP

TURP (1) Laser enucleaon Bipolar enucleaon Laser vaporisaon PU liˆ

Open prostatectomy (1) HoLEP (1) Bipolar enucleaon (1) Laser vaporisaon Thulium enucleaon TURP

Laser vaporisaon (1) Laser enucleaon

PU liˆ

(1) Current standard/first choice. The alternative treatments are presented in alphabetical order. Laser vaporisation includes GreenLight, thulium, and diode laser vaporisation. Laser enucleation includes holmium and thulium laser enucleation. HoLEP = holmium laser enucleation; TUIP = transurethral incision of the prostate; TURP = transurethral resection of the prostate and PU = prostatic urethral.

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5.5

Management of Nocturia in men with lower urinary tract symptoms

The following section reports a SR of therapy for the management of nocturia in men with LUTS. It also emphasises the need to consider the wide range of possible causes of nocturia [495]. Nocturia is defined as the complaint of waking at night to void [6]. It reflects the relationship between the amount of urine produced while asleep, and the ability of the bladder to store the urine received. Nocturia can occur as part of lower urinary tract dysfunction (LUTD), such as OAB and chronic pelvic pain syndrome. Nocturia can also occur in association with other forms of LUTD, such as BOO, but here it is debated whether the link is one of causation or simply the co-existence of two common conditions. Crucially, nocturia may have behavioural, sleep disturbance (primary or secondary) or systemic causes unrelated to LUTD (Table 2). Differing causes often co-exist and each has to be considered in all cases. Only where LUTD is contributory should nocturia be termed a LUTS. Table 2: Categories of nocturia CATEGORY Behavioural

Disproportionate urine production (at all times, or during sleep) Inappropriate fluid intake

Systemic Sleep disorder

Water, salt and metabolite output Variable water and salt output

LUTD

Low volume of each void (at all times, or overnight) “Bladder awareness” due to secondary sleep disturbance “Bladder awareness” due to primary sleep disturbance Impaired storage function and increased filling sensation

5.5.1 Diagnostic assessment Evaluation is outlined in Figure 5; 1. Evaluate for LUTD according to the relevant guidelines. The severity and bother of individual LUTS should be identified with a symptom score, supplemented by directed questioning if needed. A validated bladder diary is mandatory. 2. Review whether behavioural factors affecting fluid balance and sleep are contributing. 3. Review of medical history and medications, including directed evaluation for key conditions, such as renal failure, diabetes mellitus, cardiac failure, and obstructive sleep apnoea. If systemic factors or sleep disorders are potentially important, consider involving appropriate medical expertise (see Figure 6). This is appropriate where a known condition is suboptimally managed, or symptoms and signs suggest an undiagnosed condition. 5.5.2 Medical conditions and sleep disorders Shared Care Pathway Causative categories for nocturia comprise [496]: 1. bladder storage problems; 2. 24-hour polyuria (> 40 mL/kg urine output over a 24-hour period); 3. nocturnal polyuria (NP; nocturnal output exceeding 20% of 24-hour urine output in the young, or 33% of urine output in people > 65 [6]); 4. sleep disorders; 5. mixed aetiology. Potentially relevant systemic conditions are those which impair physiological fluid balance, including influences on: levels of free water, salt, other solutes and plasma oncotic pressure; endocrine regulation e.g. by antidiuretic hormone; natriuretic peptides; cardiovascular and autonomic control; renal function; neurological regulation, e.g. circadian regulation of the pineal gland, and renal innervation. As nocturia is commonly referred to the specialty without full insight into cause, the urologist must review the likely mechanisms underlying a presentation with nocturia and instigate review by relevant specialties accordingly. Thus, the managing urologist needs to evaluate nocturia patients in a context where additional medical expertise is available (Table 3). They should not proceed along any LUTD management pathway unless a causative link with LUTD is justifiably suspected, and systemic or sleep abnormalities have been considered. In patients with non-bothersome nocturia, the medical evaluation (history and physical examination) should consider the possibility of early stages of systemic disease, and whether there is possibility of earlier diagnosis or therapy adjustment. Some important potentially treatable non-urological causes of nocturia include; obstructive sleep aponea, congestive cardiac failure, poorly controlled diabetes mellitus and medications (e.g. diuretics, or lithium).

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Figure 5. Evaluation of Nocturia in non-neurogenic Male LUTS. • • • • •

History (+ sexual function) Symptom Score Questionnaire Physical Examination Urinalysis PSA (if diagnosis of PCa will change the management – discuss with patient) • Measurement of PVR

Bothersome Nocturia

yes

no

Significant PVR

• US of kidneys +/- renal function assessment

• Abnormal DRE, high PSA • Haematuria • Chronic pelvic pain Evaluate according to relevant guidelines or clinical standard

Treat underlying condition or sleep disorder Offer shared care

• US assessment of prostate • Uroflowmetry • FVC with predominant storage LUTS

Mixed features Polyuria/ NP

LUTS

Medical Conditions/Sleep disorders Care Pathway

Nocturia with LUTS in benign LUT conditions

Behavioural and drug NP treatment

Behavioural and drug LUTS treatment LUTS Algorithm Interventional LUTS treatment (Indirect MoA for nocturia)

Assessment must establish whether the patient has polyuria, LUTS, a sleep disorder or a combination. Therapy may be driven by the bother it causes, but non-bothersome nocturia may warrant assessment with a frequency volume chart (indicated by the dotted line) depending on history and clinical examination since potential presence of a serious underlying medical condition must be considered. FVC = frequency volume chart; DRE = digital rectal examination; NP = nocturnal polyuria; MoA = mechanism of action; PVR = post-void residual; PSA = prostate-specific antigen; US = ultrasound.

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Table 3: Shared care pathway for nocturia, highlighting the need to manage potentially complex patients using relevant expertise for the causative factors. UROLOGICAL CONTRIBUTION Diagnosis of LUTD • Urological/LUTS evaluation • Nocturia symptom scores • Bladder diary

SHARED CARE

Conservative management Behavioural therapy • Fluid/sleep habits advice • Drugs for storage LUTS • Drugs for voiding LUTS • ISC/catherisation • Increased exercise • Leg elevation • Weight loss

Conservative management • Antidiuretic • Diuretics • Drugs to aid sleep

Interventional therapy • Therapy of refractory storage LUTS • Therapy of refractory voiding LUTS

MEDICAL CONTRIBUTION Diagnosis of conditions causing NP • Evaluate patient’s known conditions • Screening for sleep disorders • Screening for potential causes of polyuria* Management • Initiation of therapy for new diagnosis • Optimised therapy of known conditions * Potential causes of polyuria NEPHROLOGICAL DISEASE • Tubular dysfunction • Global renal dysfunction CARDIOVASCULAR DISEASE • Cardiac disease • Vascular disease ENDOCRINE DISEASE • Diabetes insipidus/mellitus • Hormones affecting diuresis/natriuresis NEUROLOGICAL DISEASE • Pituitary and renal innervation • Autonomic dysfunction RESPIRATORY DISEASE • Obstructive sleep apnoea BIOCHEMICAL • Altered blood oncotic pressure

5.5.3 Treatment for Nocturia 5.5.3.1 Antidiuretic therapy The antidiuretic hormone arginine vasopressin (AVP) plays a key role in body water homeostasis and control of urine production by binding to V2 receptors in the renal collecting ducts. Arginine vasopressin increases water re-absorption and urinary osmolality, so decreasing water excretion and total urine volume. Arginine vasopressin also has V1 receptor mediated vasoconstrictive/hypertensive effects and a very short serum halflife, which makes the hormone unsuitable for treating nocturia/nocturnal polyuria. Desmopressin is a synthetic analogue of AVP with high V2 receptor affinity and no relevant V1 receptor affinity. It has been investigated for treating nocturia [497], with specific doses, titrated dosing, differing formulations, and options for route of administration. Most studies have short follow-up. Global interpretation of existing studies is difficult due to the limitations, imprecision, heterogeneity and inconsistencies of the studies. A SR of randomised or quasi-randomised trials in men with nocturia found that desmopressin may decrease the number of nocturnal voids by -0.46 compared to placebo over short-term follow-up (up to three months); over intermediate-term follow-up (three to twelve months) there was a change of -0.85 in nocturnal voids in a substantial number of participants without increase in major adverse events [498]. Another SR of comparative trials of men with nocturia as the primary presentation and LUTS including nocturia or nocturnal polyuria found that antidiuretic therapy using dose titration was more effective than placebo in relation to nocturnal voiding frequency and duration of undisturbed sleep [495]. Adverse events include headache, hyponatremia, insomnia, dry mouth, hypertension, abdominal pain, peripheral edema, and nausea. Three studies evaluating titrated-dose desmopressin in which men were included, reported seven serious adverse events in 530 patients (1.3%), with one death. There were seventeen cases of hyponatraemia (3.2%) and seven of hypertension (1.3%). Headache was reported in 53 (10%) and nausea in fifteen (2.8%) [495]. Hyponatremia is the most important concern, especially in patients > 65 years of age, with potential life threatening consequences. Baseline values of sodium over 130 mmol/L have been used as inclusion criteria in some research protocols. Assessment of sodium levels must be undertaken at baseline, after initiation of treatment or dose titration and during treatment. Desmopressin is not recommended in high-risk groups [495].

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Desmopressin oral disintegrating tablets (ODT) have been studied separately in the sex-specific pivotal trials CS41 and CS40 in patients with nocturia [499, 500]. Almost 87% of included patients had nocturnal polyuria and approximately 48% of the patients were > 65 years. The co-primary endpoints in both trials were change in number of nocturia episodes per night from baseline and at least a 33% decrease in the mean number of nocturnal voids from baseline during three months of treatment. The mean change in nocturia episodes from baseline was greater with desmopressin ODT compared to placebo (difference: women = -0.3 [95% CI: -0.5, -0.1]; men = -0.4 [95% CI: -0.6, -0.2]). The 33% responder rate was also greater with desmopressin ODT compared to placebo (women: 78% vs. 62%; men: 67% vs. 50%). Analysis of three published placebo-controlled trials of desmopressin ODT for nocturia showed that clinically significant hyponatraemia was more frequent in patients aged ≥ 65 years than in those aged < 65 years in all dosage groups, including those receiving the minimum effective dose for desmopressin (11% of men aged ≥ 65 years vs. 0% of men aged < 65 years receiving 50 mcg; 4% of women ≥ 65 aged years vs. 2% of women aged < 65 years receiving 25 mcg). Severe hyponatraemia, defined as ≤ 125 mmol/L serum sodium, was rare, affecting 22/1,431 (2%) patients overall [501]. Low dose desmopressin (ODT) has been approved in Europe, Canada and Australia for the treatment of nocturia with ≥ 2 episodes in gender-specific low doses 50 mcg for men and 25 mcg for women; however, it initially failed to receive FDA approval, with the FDA citing uncertain benefit relative to risks as the reason. Following resubmission to the FDA in June 2018 desmopressin acetate sublingual tablet, 50 mcg for men and 25 mcg for women, was approved for the treatment of nocturia due to nocturnal polyuria in adults who awaken at least two times per night to void with a boxed warning for hyponatremia. Desmopressin acetate nasal spray is a new low-dose formulation of desmopressin and differs from other types of desmopressin formulation due to its bioavailability and route of administration. Desmopressin acetate nasal spray has been investigated in two RCTs including men and women with nocturia (over two episodes per night) and a mean age of 66 years. The average benefit of treatment relative to placebo was statistically significant but low, -0.3 and -0.2 for the 1.5 mcg and 0.75 mcg doses of desmopressin acetate, respectively. The number of patients with a reduction of more than 50% of nocturia episodes was 48.5% and 37.9%, respectively compared with 30% in the placebo group [502]. The reported adverse event rate of the studies was rather low and the risk of hyponatremia was 1.2% and 0.9% for desmopressin acetate 1.5 mcg and 0.75 mcg, respectively. Desmopressin acetate nasal spray was approved by the FDA in 2017 for the treatment of nocturia due to nocturnal polyuria, but it is not available in Europe. Practical considerations A complete medical assessment should be made, to exclude potentially non-urological underlying causes, e.g. sleep apnea, before prescribing desmopressin in men with nocturia due to nocturnal polyuria. The optimal dose differs between patients, in men < 65 years desmopressin treatment should be initiated at a low dose (0.1 mg/day) and may be gradually increased up to a dosage of 0.4 mg/day every week until maximum efficacy is reached. Desmopressin is taken once daily before sleeping. Patients should avoid drinking fluids at least one hour before and for eight hours after dosing. Low dose desmopressin may be prescribed in patients > 65 years. In men ≥ 65 years or older, low dose desmopressin should not be used if the serum sodium concentration is below normal: all patients should be monitored for hyponatremia. Urologists should be cautious when prescribing low-dose desmopressin in patients under-represented in trials (e.g. patients > 75 years) who may have an increased risk of hyponatremia. 5.5.3.2 Medications to treat LUTD Where LUTD is diagnosed and considered causative of nocturia, relevant medications for storage (and voiding) LUTS may be considered. Applicable medications include; selective α1-adrenergic antagonists [503], antimuscarinics [504-506], 5-ARIs [507] and PDE5Is [508]. However, effect size of these medications is generally small, or not significantly different from placebo when used to treat nocturia [495]. Data on OAB medications (antimuscarinics, beta-3 agonist) generally had a female-predominant population. No studies specifically addressing the impact of OAB medications on nocturia in men were identified [495]. Benefits with combination therapies were not consistently observed. 5.5.3.3 Other medications Agents to promote sleep [509], diuretics [510], non-steroidal anti-inflammatory agents (NSAIDs) [511] and phytotherapy [512] were reported as being associated with response or QoL improvement [495]. Effect size of these medications in nocturia is generally small, or not significantly different from placebo. Larger responses have been reported for some medications, but larger scale confirmatory RCTs are lacking. Agents to promote sleep do not appear to reduce nocturnal voiding frequency, but may help patients return to sleep.

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Summary of evidence No clinical trial of pathophysiology-directed primary therapy has been undertaken. No robust clinical trial of behavioural therapy as primary intervention has been undertaken. Antidiuretic therapy reduces nocturnal voiding frequency in men with baseline severity of two or more voids per night. There is an increased risk of hyponatremia in patients 65 years of age or older under antidiuretic therapy. Antidiuretic therapy increases duration of undisturbed sleep. Alpha 1-blocker use is associated with improvements in undisturbed sleep duration and nocturnal voiding frequency, which are generally of only marginal clinical significance. Antimuscarinic medications can reduce night-time urinary urgency severity, but the reduction in overall nocturia frequency is small or non-significant. Antimuscarinic medications are associated with higher incidence of dry mouth compared with placebo. 5α-reductase inhibitors reduce nocturia severity in men with baseline nocturia severity of two or more voids per night. A trial of timed diuretic therapy may be offered to men with nocturia due to nocturnal polyuria. Screening for hyponatremia should be undertaken at baseline and during treatment.

LE 4 4 1b 1b 1b 2 2 2 2 1b

Recommendations Treat underlying causes of nocturia, including behavioural, systemic condition(s), sleep disorders, lower urinary tract dysfunction, or a combination of factors. Discuss behavioural changes with the patient to reduce nocturnal urine volume and episodes of nocturia, and improve sleep quality. Offer desmopressin to decrease nocturia due to nocturnal polyuria in men < 65 years of age.

Strength rating Weak

Offer low dose desmopressin for men > 65 years of age with nocturia at least twice per night due to nocturnal polyuria. Screen for hyponatremia at baseline, day three and day seven, one month after initiating therapy and periodically during treatment. Measure serum sodium more frequently in patients > 65 years of age and in patients at increased risk of hyponatremia. Discuss with the patient the potential clinical benefit relative to the associated risks from the use of desmopressin, especially in men > 65 years of age. Offer α1-adrenergic antagonists for treating nocturia in men who have nocturia associated with LUTS. Offer antimuscarinic drugs for treating nocturia in men who have nocturia associated with overactive bladder. Offer 5α-reductase inhibitors for treating nocturia in men who have nocturia associated with LUTS and an enlarged prostate (> 40 mL). Do not offer phosphodiesterase type 5 inhibitors for the treatment of nocturia.

Weak

6.

FOLLOW-UP

6.1

Watchful waiting (behavioural)

Weak Weak

Strong

Strong Weak Weak Weak Weak

Patients who elect to pursue a WW policy should be reviewed at six months and then annually, provided there is no deterioration of symptoms or development of absolute indications for surgical treatment. The following are recommended at follow-up visits: history, IPSS, uroflowmetry, and PVR volume.

6.2

Medical treatment

Patients receiving α1-blockers, muscarinic receptor antagonists, beta-3 agonists, PDE5Is or the combination of α1-blockers and 5-ARIs or muscarinic receptor antagonists should be reviewed four to six weeks after drug initiation to determine the treatment response. If patients gain symptomatic relief in the absence of troublesome adverse events, drug therapy may be continued. Patients should be reviewed at six months and then annually, provided there is no deterioration of symptoms or development of absolute indications for surgical treatment. The following are recommended at follow-up visits: history, IPSS, uroflowmetry, and PVR volume. Frequency volume charts or bladder diaries should be used to assess response to treatment for predominant storage symptoms or nocturnal polyuria.

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Patients receiving 5-ARIs should be reviewed after twelve weeks and six months to determine their response and adverse events. The following are recommended at follow-up visits: history, IPSS, uroflowmetry and PVR volume. Men taking 5-ARIs should be followed up regularly using serial PSA testing if life expectancy is greater than ten years and if a diagnosis of PCa could alter management. A new baseline PSA should be determined at six months, and any confirmed increase in PSA while on 5-ARIs should be evaluated. In patients receiving desmopressin, serum sodium concentration should be measured at day three and seven, one month after initiating therapy and periodically during treatment. If serum sodium concentration has remained normal during periodic screening follow-up screening can be carried out every three months subsequently. However, serum sodium concentration should be monitored more frequently in patients ≥ 65 years of age and in patients at increased risk of hyponatremia. The following tests are recommended at followup visits: serum-sodium concentration and FVC. The follow-up sequence should be restarted after dose escalation.

6.3

Surgical treatment

After prostate surgery, patients should be reviewed four to six weeks after catheter removal to evaluate treatment response and adverse events. If patients have symptomatic relief and are without adverse events, no further re-assessment is necessary. The following tests are recommended at follow-up visit after four to six weeks: IPSS, uroflowmetry and PVR volume. Summary of evidence LE Follow-up for all conservative, medical, or operative treatment modalities is based on empirical data or 4 theoretical considerations, but not on evidence-based studies. Recommendations Follow-up all patients who receive conservative, medical or surgical management.

Strength rating Weak

Define follow-up intervals and examinations according to the specific treatment.

Weak

7.

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Gratzke, C., et al. Prostatic urethral lift vs transurethral resection of the prostate: 2-year results of the BPH6 prospective, multicentre, randomized study. BJU Int, 2017. 119: 767. https://www.ncbi.nlm.nih.gov/pubmed/27862831 Rukstalis, D., et al. Prostatic Urethral Lift (PUL) for obstructive median lobes: 12 month results of the MedLift Study. Prostate Cancer Prostatic Dis, 2019. 22: 411. https://www.ncbi.nlm.nih.gov/pubmed/30542055 Magistro, G., et al. New intraprostatic injectables and prostatic urethral lift for male LUTS. Nat Rev Urol, 2015. 12: 461. https://www.ncbi.nlm.nih.gov/pubmed/26195444 Marberger, M., et al. A randomized double-blind placebo-controlled phase 2 dose-ranging study of onabotulinumtoxinA in men with benign prostatic hyperplasia. Eur Urol, 2013. 63: 496. https://www.ncbi.nlm.nih.gov/pubmed/23098762 McVary, K.T., et al. A multicenter, randomized, double-blind, placebo controlled study of onabotulinumtoxinA 200 U to treat lower urinary tract symptoms in men with benign prostatic hyperplasia. J Urol, 2014. 192: 150. https://www.ncbi.nlm.nih.gov/pubmed/24508634 Shim, S.R., et al. Efficacy and safety of botulinum toxin injection for benign prostatic hyperplasia: a systematic review and meta-analysis. Int Urol Nephrol, 2016. 48: 19. https://www.ncbi.nlm.nih.gov/pubmed/26560471 Elhilali, M.M., et al. Prospective, randomized, double-blind, vehicle controlled, multicenter phase IIb clinical trial of the pore forming protein PRX302 for targeted treatment of symptomatic benign prostatic hyperplasia. J Urol, 2013. 189: 1421. https://www.ncbi.nlm.nih.gov/pubmed/23142202 Denmeade, S.R., et al. Phase 1 and 2 studies demonstrate the safety and efficacy of intraprostatic injection of PRX302 for the targeted treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol, 2011. 59: 747. https://www.ncbi.nlm.nih.gov/pubmed/21129846 Shore, N., et al. Fexapotide triflutate: results of long-term safety and efficacy trials of a novel injectable therapy for symptomatic prostate enlargement. World J Urol, 2018. 36: 801. https://www.ncbi.nlm.nih.gov/pubmed/29380128 Porpiglia, F., et al. Temporary implantable nitinol device (TIND): a novel, minimally invasive treatment for relief of lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH): feasibility, safety and functional results at 1 year of follow-up. BJU Int, 2015. 116: 278. https://www.ncbi.nlm.nih.gov/pubmed/25382816 Porpiglia, F., et al. 3-Year follow-up of temporary implantable nitinol device implantation for the treatment of benign prostatic obstruction. BJU Int, 2018. 122: 106. https://www.ncbi.nlm.nih.gov/pubmed/29359881 Sakalis, V.I., et al. Medical Treatment of Nocturia in Men with Lower Urinary Tract Symptoms: Systematic Review by the European Association of Urology Guidelines Panel for Male Lower Urinary Tract Symptoms. Eur Urol, 2017. 72: 757. https://www.ncbi.nlm.nih.gov/pubmed/28666669 Marshall, S.D., et al. Nocturia: Current Levels of Evidence and Recommendations From the International Consultation on Male Lower Urinary Tract Symptoms. Urology, 2015. https://www.ncbi.nlm.nih.gov/pubmed/25881866 Cannon, A., et al. Desmopressin in the treatment of nocturnal polyuria in the male. BJU Int, 1999. 84: 20. https://www.ncbi.nlm.nih.gov/pubmed/10444118 Han, J., et al. Desmopressin for treating nocturia in men. Cochrane Database Syst Rev, 2017. 10: CD012059. https://www.ncbi.nlm.nih.gov/pubmed/29055129 Weiss, J.P., et al. Efficacy and safety of low dose desmopressin orally disintegrating tablet in men with nocturia: results of a multicenter, randomized, double-blind, placebo controlled, parallel group study. J Urol, 2013. 190: 965. https://www.ncbi.nlm.nih.gov/pubmed/23454402 Sand, P.K., et al. Efficacy and safety of low dose desmopressin orally disintegrating tablet in women with nocturia: results of a multicenter, randomized, double-blind, placebo controlled, parallel group study. J Urol, 2013. 190: 958. https://www.ncbi.nlm.nih.gov/pubmed/23454404

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501.

502.

503.

504.

505.

506.

507.

508.

509.

510.

511.

512.

8.

Juul, K.V., et al. Low-dose desmopressin combined with serum sodium monitoring can prevent clinically significant hyponatraemia in patients treated for nocturia. BJU Int, 2017. 119: 776. https://www.ncbi.nlm.nih.gov/pubmed/27862898 Cohn, J.A., et al. Desmopressin acetate nasal spray for adults with nocturia. Expert Rev Clin Pharmacol, 2017. 10: 1281. https://www.ncbi.nlm.nih.gov/pubmed/29048257 Djavan, B., et al. The impact of tamsulosin oral controlled absorption system (OCAS) on nocturia and the quality of sleep: Preliminary results of a pilot study. Eur Urol Suppl, 2005. 4: 1119. https://www.eu-openscience.europeanurology.com/article/S1569-9056(04)00127-7/fulltext Yokoyama, O., et al. Efficacy of fesoterodine on nocturia and quality of sleep in Asian patients with overactive bladder. Urology, 2014. 83: 750. https://www.ncbi.nlm.nih.gov/pubmed/24518285 Yokoyama, O., et al. Efficacy of solifenacin on nocturia in Japanese patients with overactive bladder: impact on sleep evaluated by bladder diary. J Urol, 2011. 186: 170. https://www.ncbi.nlm.nih.gov/pubmed/21575976 Johnson, T.M., 2nd, et al. The effect of doxazosin, finasteride and combination therapy on nocturia in men with benign prostatic hyperplasia. J Urol, 2007. 178: 2045. https://www.ncbi.nlm.nih.gov/pubmed/17869295 Oelke, M., et al. Impact of dutasteride on nocturia in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH): a pooled analysis of three phase III studies. World J Urol, 2014. 32: 1141. https://www.ncbi.nlm.nih.gov/pubmed/24903347 Oelke, M., et al. Effects of tadalafil on nighttime voiding (nocturia) in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a post hoc analysis of pooled data from four randomized, placebo-controlled clinical studies. World J Urol, 2014. 32: 1127. https://www.ncbi.nlm.nih.gov/pubmed/24504761 Drake, M.J., et al. Melatonin pharmacotherapy for nocturia in men with benign prostatic enlargement. J Urol, 2004. 171: 1199. https://www.ncbi.nlm.nih.gov/pubmed/14767300 Reynard, J.M., et al. A novel therapy for nocturnal polyuria: a double-blind randomized trial of frusemide against placebo. Br J Urol, 1998. 81: 215. https://www.ncbi.nlm.nih.gov/pubmed/9488061 Falahatkar, S., et al. Celecoxib for treatment of nocturia caused by benign prostatic hyperplasia: a prospective, randomized, double-blind, placebo-controlled study. Urology, 2008. 72: 813. https://www.ncbi.nlm.nih.gov/pubmed/18692876 Sigurdsson, S., et al. A parallel, randomized, double-blind, placebo-controlled study to investigate the effect of SagaPro on nocturia in men. Scand J Urol, 2013. 47: 26. https://www.ncbi.nlm.nih.gov/pubmed/23323790

CONFLICT OF INTEREST

All members of the EAU Non-neurogenic Male LUTS Guidelines Panel have provided disclosure statements on all relationships that they have that might be perceived to be a potential source of a conflict of interest. This information is publically accessible through the EAU website: http://www.uroweb.org/guidelines/. These Guidelines were developed with the financial support of the EAU. No external sources of funding and support have been involved. The EAU is a non-profit organisation, and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

9.

CITATION INFORMATION

The format in which to cite the EAU Guidelines will vary depending on the style guide of the journal in which the citation appears. Accordingly, the number of authors or whether, for instance, to include the publisher, location, or an ISBN number may vary.

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The compilation of the complete Guidelines should be referenced as: EAU Guidelines. Edn. presented at the EAU Annual Congress Milan 2021. ISBN 978-94-92671-13-4. If a publisher and/or location is required, include: EAU Guidelines Office, Arnhem, the Netherlands. http://uroweb.org/guidelines/compilations-of-all-guidelines/ References to individual guidelines should be structured in the following way: Contributors’ names. Title of resource. Publication type. ISBN. Publisher and publisher location, year.

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EAU Guidelines on

Muscle-invasive and Metastatic Bladder Cancer J.A. Witjes (Chair), H.M. Bruins, R. Cathomas, E. Compérat, N.C. Cowan, J.A. Efstathiou, R. Fietkau, G. Gakis, V. Hernández, A. Lorch, M.I. Milowsky, M.J. Ribal (Vice-chair), G.N. Thalmann, A.G. van der Heijden, E. Veskimäe Guidelines Associates: E. Linares Espinós, M. Rouanne, Y. Neuzillet

© European Association of Urology 2021

TABLE OF CONTENTS

PAGE

1. INTRODUCTION 1.1 Aims and scope 1.2 Panel composition 1.3 Available publications 1.4 Publication history and summary of changes 1.4.1 Publication history 1.4.2 Summary of changes

6 6 6 6 6 6 6

2. METHODS 2.1 Data identification 2.2 Peer-review 2.2.1 Lay review 2.3 Future goals

9 9 10 10 11

3. EPIDEMIOLOGY, AETIOLOGY AND PATHOLOGY 3.1 Epidemiology 3.2 Aetiology 3.2.1 Tobacco smoking 3.2.2 Occupational exposure to chemicals 3.2.3 Radiotherapy 3.2.4 Dietary factors 3.2.5 Metabolic disorders 3.2.6 Bladder schistosomiasis and chronic urinary tract infection 3.2.7 Gender 3.2.8 Genetic factors 3.2.9 Summary of evidence and guidelines for epidemiology and risk factors 3.3 Pathology 3.3.1 Handling of transurethral resection and cystectomy specimens 3.3.2 Pathology of muscle-invasive bladder cancer 3.3.3 Guidelines for the assessment of tumour specimens 3.3.4 EAU-ESMO consensus statements on the management of advanced- and variant bladder cancer

11 11 11 11 11 11 12 12 12 12 13 13 13 13 14 14

4.

15 15 15

STAGING AND CLASSIFICATION SYSTEMS 4.1 Pathological staging 4.2 Tumour, node, metastasis classification

5. DIAGNOSTIC EVALUATION 5.1 Primary diagnosis 5.1.1 Symptoms 5.1.2 Physical examination 5.1.3 Bladder imaging 5.1.4 Urinary cytology 5.1.5 Cystoscopy 5.1.6 Transurethral resection of invasive bladder tumours 5.1.7 Concomitant prostate cancer 5.1.8 Summary of evidence and guidelines for the primary assessment of presumably invasive bladder tumours 5.1.9 EAU-ESMO consensus statements on the management of advanced- and variant bladder cancer 5.2 Imaging for staging of MIBC 5.2.1 Local staging of MIBC 5.2.1.1 CT imaging for local staging of MIBC 5.2.2 Imaging of lymph nodes in MIBC 5.2.3 Upper urinary tract urothelial carcinoma 5.2.3.1 Computed tomography urography 5.2.3.2 Magnetic resonance urography 5.2.4 Distant metastases at sites other than lymph nodes

2

15

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5.2.5 Future developments 5.2.6 Summary of evidence and guidelines for staging in muscle-invasive bladder cancer 5.3 MIBC and health status 5.3.1 Evaluation of comorbidity, frailty and cognition 5.3.2 Comorbidity scales, anaesthetic risk classification and geriatric assessment 5.3.3 Summary of evidence and guidelines for comorbidity scales

20 20 20 22 23

6. MARKERS 6.1 Introduction 6.2 Prognostic markers 6.2.1 Histopathological and clinical markers 6.2.2 Molecular markers 6.2.2.1 Molecular subtypes based on the Cancer Genome Atlas cohort 6.3 Predictive markers 6.3.1 Clinical and histopathological markers 6.3.2 Molecular markers 6.4 Conclusion 6.5 Summary of evidence and recommendations for urothelial markers

24 24 24 24 24 24 25 25 25 26 26

7. DISEASE MANAGEMENT 7.1 Neoadjuvant therapy 7.1.1 Introduction 7.1.2 Role of cisplatin-based chemotherapy 7.1.2.1 Summary of available data 7.1.3 The role of imaging and predictive biomarkers 7.1.4 Role of neoadjuvant immunotherapy 7.1.5 Summary of evidence and guidelines for neoadjuvant therapy 7.2 Pre- and post-operative radiotherapy in muscle-invasive bladder cancer 7.2.1 Post-operative radiotherapy 7.2.2 Pre-operative radiotherapy 7.2.3 Summary of evidence and guidelines for pre- and post-operative radiotherapy 7.2.4 EAU-ESMO consensus statements on the management of advanced- and variant bladder cancer 7.3 Radical surgery and urinary diversion 7.3.1 Removal of the tumour-bearing bladder 7.3.1.1 Introduction 7.3.1.2 Radical cystectomy: timing 7.3.2 Radical cystectomy: indications 7.3.3 Radical cystectomy: technique and extent 7.3.3.1 Radical cystectomy in men 7.3.3.1.1 Summary of evidence and recommendations for sexual preserving techniques in men 7.3.3.2 Radical cystectomy in women 7.3.3.2.1 Summary of evidence and recommendations for sexual preserving techniques in women 7.3.4 Lymphadenectomy: role and extent 7.3.5 Laparoscopic/robotic-assisted laparoscopic cystectomy 7.3.5.1 Laparoscopic radical cystectomy versus robot-assisted radical cystectomy 7.3.5.2 Summary of evidence and guidelines for laparoscopic/robotic assisted laparoscopic cystectomy 7.3.6 Urinary diversion after radical cystectomy 7.3.6.1 Patient selection and preparations for surgery 7.3.6.2 Different types of urinary diversion 7.3.6.2.1 Uretero-cutaneostomy 7.3.6.2.2 Ileal conduit 7.3.6.2.3 Orthotopic neobladder 7.3.7 Morbidity and mortality 7.3.8 Survival

26 26 26 26 27 28 28 28 29 29 29 30

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19

30 30 30 30 30 31 31 31 32 32 32 33 33 34 35 35 35 36 36 37 37 37 39

3

7.3.9 Impact of hospital and surgeon volume on treatment outcomes 7.3.10 Summary of evidence and guidelines for radical cystectomy and urinary diversion 7.3.11 EAU-ESMO consensus statements on the management of advanced and variant bladder cancer 7.4 Unresectable tumours 7.4.1 Palliative cystectomy for muscle-invasive bladder carcinoma 7.4.1.1 Guidelines for unresectable tumours 7.4.1.2 EAU-ESMO consensus statements on the management of advanced and variant bladder cancer 7.4.2 Supportive care 7.4.2.1 Obstruction of the upper urinary tract 7.4.2.2 Bleeding and pain 7.5 Bladder-sparing treatments for localised disease 7.5.1 Transurethral resection of bladder tumour 7.5.1.1 Guideline for transurethral resection of bladder tumour 7.5.1.2 EAU-ESMO consensus statements on the management of advanced and variant bladder cancer 7.5.2 External beam radiotherapy 7.5.2.1 Summary of evidence and guideline for external beam radiotherapy 7.5.2.2 EAU-ESMO consensus statements on the management of advanced and variant bladder cancer 7.5.3 Chemotherapy 7.5.3.1 Summary of evidence and guideline for chemotherapy 7.5.4 Trimodality bladder-preserving treatment 7.5.4.1 Summary of evidence and guidelines for trimodality bladder preserving treatment 7.5.4.2 EAU-ESMO consensus statements on the management of advanced and variant bladder cancer 7.6 Adjuvant therapy 7.6.1 Role of adjuvant platinum-based chemotherapy 7.6.2 Role of adjuvant immunotherapy 7.6.3 Guidelines for adjuvant therapy 7.7 Metastatic disease 7.7.1 Introduction 7.7.1.1 Prognostic factors and treatment decisions 7.7.1.2 Comorbidity in metastatic disease 7.7.2 First-line systemic therapy for metastatic disease 7.7.2.1 Definitions: ‘Fit for cisplatin, fit for carboplatin, unfit for any platinum based chemotherapy’ 7.7.2.2 Chemotherapy in patients fit for cisplatin 7.7.2.3 Chemotherapy in patients fit for carboplatin (but unfit for cisplatin) 7.7.2.4 Integration of immunotherapy in the first-line treatment of patients fit for platinum-based chemotherapy 7.7.2.4.1 Immunotherapy combination approaches 7.7.2.4.2 Use of single-agent immunotherapy 7.7.2.4.3 Switch maintenance with immunotherapy 7.7.2.5 Treatment of patients unfit for any platinum-based chemotherapy 7.7.2.6 Non-platinum combination chemotherapy 7.7.3 Second-line systemic therapy for metastatic disease 7.7.3.1 Second-line chemotherapy 7.7.3.2 Second-line immunotherapy for platinum-pre-treated patients 7.7.3.2.1 Side-effect profile of immunotherapy 7.7.4 Novel agents for second- or later-line therapy 7.7.5 Post-chemotherapy surgery and oligometastatic disease 7.7.6 Treatment of patients with bone metastases 7.7.7 Summary of evidence and guidelines for metastatic disease 7.8 Quality of life 7.8.1 Introduction 7.8.2 Neoadjuvant chemotherapy

4

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7.8.3 7.8.4 7.8.5 7.8.6

Radical cystectomy and urinary diversion Bladder sparing trimodality therapy Non-curative or metastatic bladder cancer Summary of evidence and recommendations for health-related quality of life

56 56 56 56

8. FOLLOW-UP 8.1 Follow-up in muscle invasive bladder cancer 8.2 Site of recurrence 8.2.1 Local recurrence 8.2.2 Distant recurrence 8.2.3 Urothelial recurrences 8.3 Time schedule for surveillance 8.4 Follow-up of functional outcomes and complications 8.5 Summary of evidence and recommendations for specific recurrence sites 8.6 EAU-ESMO consensus statements on the management of advanced- and variant bladder cancer

57 57 57 57 57 58 58 58 59

9.

REFERENCES

60

10.

CONFLICT OF INTEREST

94

11.

CITATION INFORMATION

94

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59

5

1.

INTRODUCTION

1.1

Aims and scope

The European Association of Urology (EAU) Guidelines Panel for Muscle-invasive and Metastatic Bladder Cancer (MIBC) have prepared these guidelines to help urologists assess the evidence-based management of MIBC and to incorporate guideline recommendations into their clinical practice. Separate EAU guidelines documents are available addressing upper urinary tract (UUT) tumours [1], non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ) (NMIBC) [2], and primary urethral carcinomas [3]. It must be emphasised that clinical guidelines present the best evidence available to the experts but following guideline recommendations will not necessarily result in the best outcome. Guidelines can never replace clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions - also taking personal values and preferences/individual circumstances of patients into account. Guidelines are not mandates and do not purport to be a legal standard of care.

1.2

Panel composition

The EAU Guidelines Panel consists of an international multidisciplinary group of clinicians, including urologists, oncologists, a pathologist, a radiologist and radiotherapists. Section 5.3 -MIBC and health status, was developed with the assistance of Dr. S. O’Hanlon, consultant geriatrician, International Society of Geriatric Oncology (SIOG) representative and member of the EAU-EANM-ESTRO-ESUR-SIOG Prostate Cancer Guidelines Panel. The MIBC Panel is most grateful for his support. All experts involved in the production of this document have submitted potential conflict of interest statements which can be viewed on the EAU website Uroweb: http://uroweb.org/guideline/ bladdercancermuscle-invasive-and-metastatic/?type=panel.

1.3

Available publications

A quick reference document (Pocket Guidelines) is available, both in print and as an app for iOS and Android devices. These are abridged versions which may require consultation together with the full text version. Several scientific publications are available (the most recent paper dating back to 2020 [4]), as are a number of translations of all versions of the EAU MIBC Guidelines. All documents are accessible through the EAU website: http://uroweb.org/guideline/bladder-cancer-muscle-invasive-and-metastatic/.

1.4

Publication history and summary of changes

1.4.1 Publication history The EAU published its first guidelines on bladder cancer (BC) in 2000. This document covered both NMIBC and MIBC. Since these conditions require different treatment strategies, it was decided to give each condition its own guidelines, resulting in the first publication of the MIBC Guidelines in 2004. This 2021 document presents a limited update of the 2020 version. 1.4.2 Summary of changes New relevant references have been identified through a structured assessment of the literature and incorporated in the various chapters of the 2021 EAU MIBC Guidelines resulting in new sections and added and revised recommendations in: •

Section 3.3.3 Guidelines for the assessment of tumour specimens Recommendation Record the sampling sites, as well as information on tumour size when providing specimens to the pathologist.

•

Strength rating Strong

 ection 5.1.8 Summary of evidence and guidelines for the primary assessment of presumably invasive S bladder tumours Summary of evidence LE In men, prostatic urethral biopsy includes resection from the bladder neck to the verumontanum 2b (between the 5 and 7 o’clock position) using a resection loop. In case any abnormal-looking areas in the prostatic urethra are present at this time, these need to be biopsied as well.

6

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Recommendations In men with a negative prostatic urethral biopsy undergoing subsequent orthotopic neobladder construction, an intra-operative frozen section can be omitted. In men with a prior positive transurethral prostatic biopsy, subsequent orthotopic neobladder construction should not be denied a priori, unless an intra-operative frozen section of the distal urethral stump reveals malignancy at the level of urethral dissection.

Strength rating Strong Strong

•

Section 5.2.1 - Local staging of MIBC; inclusion of data on multiparametric MRI using the Vesical Imaging Reporting and Data System (VI-RADS) scoring system. No new recommendation has been provided.

•

Section 5.3 - MIBC and health status; this section has been updated, introducing the concept of frailty.

•

Chapter 6 - Markers; this chapter has been significantly revised, presenting two new recommendations. 6.5 Summary of evidence and recommendations for urothelial markers Summary of evidence There is insufficient evidence to use TMB, molecular subtypes, immune or other gene expression signatures for the management of patients with urothelial cancer. Recommendations Evaluate PD-L1 expression (by immunohistochemistry) to determine the potential for use of pembrolizumab or atezolizumab in previously untreated patients with locally advanced or metastatic urothelial cancer who are unfit for cisplatin-based chemotherapy. Evaluate for FGFR2/3 genetic alterations for the potential use of erdafitinib in

LE -

Strength rating Weak

Weak

patients with locally advanced or metastatic urothelial carcinoma who have progressed following platinum-containing chemotherapy (including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy).

•

 .2 - Pre- and post-operative radiotherapy in muscle-invasive bladder cancer; this section was revised 7 and new data added, resulting in an additional recommendation. 7.2.3 Summary of evidence and guidelines for pre- and post-operative radiotherapy Summary of evidence Addition of adjuvant RT to chemotherapy is associated with an improvement in local relapsefree survival following cystectomy for locally advanced bladder cancer (pT3b─4, or nodepositive).

LE 2a

Recommendation Strength rating Consider offering adjuvant radiation in addition to chemotherapy following radical Weak cystectomy, based on pathologic risk (pT3b–4, or positive nodes, or positive margins).

7.3.10 Summary of evidence and guidelines for radical cystectomy and urinary diversion Summary of evidence Ensuring that patients are well informed about the various urinary diversion options prior to making a decision may help prevent or reduce decision regret, independent of the method of diversion selected.

LE 3

•

7.5.4 Trimodality bladder-preserving treatment

•

7.7 Metastatic disease: data from a number of key trials has been included, in particular on immunotherapy combinations in first- and later-line setting, resulting in a number of new recommendations and a change to the treatment flowchart (Figure 7.2).

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7

7.7.8 Summary of evidence and guidelines for metastatic disease Summary of evidence LE PD-1 inhibitor pembrolizumab has been approved for patients that have progressed during or after previous platinum-based chemotherapy based on the results of a phase III trial. PD-L1 inhibitors atezolizumab, nivolumab, durvalumab and avelumab have been FDA approved for patients that have progressed during or after previous platinum-based chemotherapy based on the results of a phase II trial. PD-1 inhibitor pembrolizumab and PD-L1 inhibitor atezolizumab have been approved for patients with advanced or metastatic UC unfit for cisplatinum-based first-line chemotherapy and with overexpression of PD-L1 based on the results of single-arm phase II trials. The combination of chemotherapy plus pembrolizumab or atezolizumab and the combination of durvalumab and tremelimumab have not demonstrated an OS survival benefit compared to platinum-based chemotherapy alone. Switch maintenance with the PD-L1 inhibitor avelumab has demonstrated significant OS benefit in patients achieving at least stable disease on first-line platinum-based chemotherapy. Recommendations First-line treatment for platinum-fit patients Use cisplatin-containing combination chemotherapy with GC or HD-MVAC. In patients unfit for cisplatin but fit for carboplatin use the combination of carboplatin and gemcitabine. In patients achieving stable disease, or better, after first-line platinum-based chemotherapy use maintenance treatment with PD-L1 inhibitor avelumab. First-line treatment in patients unfit for platinum-based chemotherapy Consider checkpoint inhibitors pembrolizumab or atezolizumab. Second-line treatment Offer checkpoint inhibitor pembrolizumab to patients progressing during, or after, platinum-based combination chemotherapy for metastatic disease. If this is not possible, offer atezolizumab, nivolumab (EMA, FDA approved); avelumab or durvalumab (FDA approved). Further treatment after platinum- and immunotherapy Offer treatment in clinical trials testing novel antibody drug conjugates (enfortumab vedotin, sacituzumab govitecan); or in case of patients with FGFR3 alterations, FGFR tyrosine kinase inhibitors.

Strength rating Strong Strong Strong

Weak Strong

Strong

GC = gemcitabine plus cisplatin; FGFR = fibroblast growth factor receptor; HD-MVAC = high-dose intensity methotrexate, vinblastine, adriamycin plus cisplatin.

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Figure 7.2: Flow chart for the management of metastatic urothelial cancer*

PLATINUM-INELIGIBLE

PLATINUM-ELIGIBLE cisplatin

PS 2 and GFR < 60 mL/min PS > 2; GFR < 30 mL/min

carboplatin

PS 0-1 and GFR > 50-60 mL/min

PS 2 or GFR 30-60 mL/min

cisplatin/gemcitabine or DD-MVAC 4-6 cycles

carboplatin/gemcitabine 4-6 cycles

PD

PD-L1 +

PD-L1 -

CR/PR/SD

2nd line therapy

PD

Watchful waiting

Maintenance

• pembrolizumab (atezolizumab, avelumab, durvalumab, nivolumab) • Trials

Switch maintenance: avelumab

Immunotherapy • atezolizumab • pembrolizumab

Best supportive care

LATER-LINE THERAPY UC patients refractory to platinum-based chemotherapy and IO

FGFR3 mutation UC progressing on platinum-based chemotherapy ± prior IO

• •

•

erdafitinib (FDA) – in trial chemotherapy: o paclitaxel o Docetaxel o vinflunine Trials

• •

•

enfortumab vedotin (FDA) – in trial chemotherapy: o paclitaxel o docetaxel o vinflunine Trials

*Treatment within clinical trials is highly encouraged. BSC = best supportive care; CR = complete response; DD-MVAC = dose dense methotrexate vinblastine doxorubicin cisplatin; EV = enfortumab vedotin; FDA = US Food and Drug Administration; FGFR = pan-fibroblast growth factor receptor tyrosine kinase inhibitor; GFR = glomerular filtration rate; IO = immunotherapy; PR = partial response; PS = performance status; SD = stable disease.

2.

METHODS

2.1

Data identification

For the 2021 MIBC Guidelines, new and relevant evidence has been identified, collated and appraised through a structured assessment of the literature. A broad and comprehensive literature search, covering all sections of the MIBC Guideline was performed. The search was limited to English language publications. Databases searched included Medline, EMBASE and the Cochrane Libraries, covering a time frame between May 10th, 2019 and May 14th, 2020. A total of 1,837 unique records were identified, retrieved and screened for relevance resulting in 83 new publications having been included in the 2021 print. A detailed search strategy is available online: http://uroweb.org/guideline/bladdercancer-muscle-invasive-andmetastatic/?type=appendices-publications.

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9

For each recommendation within the guidelines there is an accompanying online strength rating form, the basis of which is a modified GRADE methodology [5, 6] which addresses a number of key elements namely: 1. the overall quality of the evidence which exists for the recommendation, references used in this text are grade according to a classification system modified from the Oxford Centre for Evidence-Based Medicine Levels of Evidence [7]; 2. the magnitude of the effect (individual or combined effects); 3. the certainty of the results (precision, consistency, heterogeneity and other statistical or study related factors); 4. the balance between desirable and undesirable outcomes; 5. the impact of patient values and preferences on the intervention; 6. the certainty of those patient values and preferences. These key elements are the basis which panels use to define the strength rating of each recommendation. The strength of each recommendation is represented by the words ‘strong’ or ‘weak’ [6]. The strength of each recommendation is determined by the balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including certainty of estimates), and nature and variability of patient values and preferences. Additional information can be found in the general Methodology section of this print, and online at the EAU website; http://www.uroweb.org/guideline/. A list of Associations endorsing the EAU Guidelines can also be viewed online at the above address. The results of a collaborative multi-stakeholder consensus project on the management of advanced and variant bladder cancer have been incorporated in the 2020 MIBC Guidelines update [8, 9]. Only statements which reached the a priori defined level of agreement - ≥ 70% agreement and ≤ 15% disagreement - across all stakeholders involved in this consensus project are listed. The methodology is presented in detail in the scientific publications. Since the publication of these consensus papers, emerging evidence prompted a re-evaluation of these findings, resulting in the removal of a number of consensus statements.

2.2

Peer-review

The 2021 print of the MIBC guidelines was peer reviewed prior to publication. 2.2.1 Lay review Post publication, the 2018 MIBC Guidelines were shared with seven patients treated for MIBC. Their comments were requested, but not limited to: • the overall tone of the guidelines content; • any missing information; • any information considered incorrect; • any information which is not presented in a clear fashion; • any text which is considered redundant and should be omitted; • any text section that should be more detailed. Common comments across reviewers: • In general, the overall tone of the text was considered informational and instructive, but the language used obviously targets medical professionals, which make certain parts of the text difficult to understand for lay persons. The use of many abbreviations is considered an additional hindrance, as are the methodological elements. In case the EAU are considering producing a lay version of this text, the language needs to be adapted and clear instructions are to be provided. • It is difficult for lay reviewers to comment on what may be omitted since, in their opinion, they lack the expertise. • Some sections, such as ‘Recurrent disease’ and ‘Markers’ denote areas where less evidence is available. Consequently, the available data is less systematically presented which makes these sections more difficult to understand. • There is an interest whether screening for BC is a consideration. • In particular ‘follow-up’, ‘quality of life’ and ‘survivorship aspects’ should be elaborated on; providing additional information on what may be expected after treatment is considered very helpful for patients and their families. Also lifestyle elements would be of relevance (healthy living, “what to do to prevent cancer”). For this section, in particular, involvement of patients in the text development was considered missing. Transparency about the process of patient involvement in guidelines development was considered most relevant. The MIBC Guidelines Panel is most grateful for the unique insights and guidance provided by the lay reviewers. 10

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2.3

Future goals

The MIBC Panel will integrate two patient advocates in the course of 2021, to ensure that patient views will be appropriately represented in the course of the production of these guidelines. Topics considered for inclusion in the 2022 update of the MIBC Guidelines: • development of a diagnostic pathway for the assessment of visible and non-visible haematuria; • participation in developing strategies to ensure meaningful participation of patients in the development and implementation of the MIBC Guidelines.

3.

EPIDEMIOLOGY, AETIOLOGY AND PATHOLOGY

3.1

Epidemiology

Bladder cancer is the 7th most commonly diagnosed cancer in males, whilst it drops to 10th position when both genders are considered [10]. The worldwide age-standardised incidence rate (per 100,000 person/years) is 9.5 for men and 2.4 for women [10]. In the European Union, the age-standardised incidence rate is 20 for men and 4.6 for women [10]. In Europe, the highest age-standardised incidence rate has been reported in Belgium (31 in men and 6.2 in women) and the lowest in Finland (18.1 in men and 4.3 in women) [10]. Worldwide, the BC age-standardised mortality rate (per 100,000 person/years) was 3.2 for men vs. 0.9 for women in 2012 [10]. Bladder cancer incidence and mortality rates vary across countries due to differences in risk factors, detection and diagnostic practices, and availability of treatments. The variations are, however, also partly caused by the different methodologies used in the studies and the quality of data collection [11, 12]. The incidence and mortality of BC has decreased in some registries, possibly reflecting the decreased impact of causative agents [12, 13]. Approximately 75% of patients with BC present with disease confined to the mucosa (stage Ta, carcinoma in situ [CIS]) or submucosa (stage T1). In younger patients (< 40 years) this percentage is even higher [14]. Patients with TaT1 and CIS have a high prevalence due to long-term survival in many cases and lower risk of cancer-specific mortality (CSM) compared to T2-4 tumours [10, 11].

3.2

Aetiology

3.2.1 Tobacco smoking Tobacco smoking is the most well-established risk factor for BC, causing 50–65% of male cases and 20–30% of female cases [15]. A causal relationship has been established between exposure to tobacco and cancer in studies in which chance, bias and confounding can be discounted with reasonable confidence [16]. The incidence of BC is directly related to the duration of smoking and the number of cigarettes smoked per day [17]. A meta-analysis looked at 216 observational studies on cigarette smoking and cancer published between 1961 and 2003, and the pooled risk estimates for BC demonstrated a significant association for both current and former smokers [18]. Recently, an increase in risk estimates for current smokers relative to never smokers has been described suggesting this could be due to changes in cigarette composition [15]. Starting to smoke at a younger age increased the risk of death from BC [19]. An immediate decrease in the risk of BC was observed in those who stopped smoking. The reduction was about 40% within one to four years of quitting smoking and 60% after 25 years of cessation [17]. Encouraging people to stop smoking would result in the incidence of BC decreasing equally in men and women [15]. 3.2.2 Occupational exposure to chemicals Occupational exposure is the second most important risk factor for BC. Work-related cases accounted for 20–25% of all BC cases in several series and it is likely to occur in occupations in which dyes, rubbers, textiles, paints, leathers, and chemicals are used [20]. The risk of BC due to occupational exposure to carcinogenic aromatic amines is significantly greater after ten years or more of exposure; the mean latency period usually exceeds 30 years [21, 22]. Population-based studies established the occupational attribution for BC in men to be 7.1%, while no such attribution was discernible for women [11, 23]. 3.2.3 Radiotherapy Increased rates of secondary bladder malignancies have been reported after external-beam radiotherapy (EBRT) for gynaecological malignancies, with relative risks (RR) of 2-4 [24]. In a population-based cohort study,

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the standardised incidence ratios for BC developing after radical prostatectomy (RP), EBRT, brachytherapy, and EBRT-brachytherapy were 0.99, 1.42, 1.10, and 1.39, respectively, in comparison with the general U.S. population [25]. It has recently been proposed that patients who have received radiotherapy (RT) for prostate cancer with modern modalities such as intensity-modulated radiotherapy (IMRT) may have lower rates of in-field bladder- and rectal secondary malignancies [26]. Nevertheless, since longer follow-up data are not yet available, and as BC requires a long period to develop, patients treated with radiation and with a long life expectancy are at a higher risk of developing BC [26]. 3.2.4 Dietary factors Several dietary factors have been related to BC; however, the links remain controversial. The European Prospective Investigation into Cancer and Nutrition (EPIC) study is an on-going multicentre cohort study designed to examine the association between diet, lifestyle, environmental factors and cancer. They found no links between BC and fluid intake, red meat, vegetable and fruit consumption and only recently an inverse association between dietary intake of flavonoids and lignans and the risk of aggressive BC tumours has been described [27]. 3.2.5 Metabolic disorders In a large prospective study pooling six cohorts from Norway, Sweden, and Austria (The Metabolic syndrome and Cancer project, Me-Can 2.0), metabolic aberrations, especially elevated blood pressure and triglycerides, were associated with increased risks of BC among men, whereas high body mass index (BMI) was associated with decreased BC risk. The associations between BMI, blood pressure and BC risk significantly differed between men and women [28]. The association of diabetes mellitus (DM) with the risk of BC has been evaluated in numerous meta-analyses with inconsistent results. When analysing specific subpopulations, DM was associated with BC or CSM risk especially in men [29]. Thiazolidinediones (pioglitazone and rosiglitazone) are oral hypoglycaemic drugs used for the management of type 2 DM. Their use and the association with BC is still a matter of debate. In a recent meta-analysis of observational studies the summary results indicated that pioglitazone use was significantly associated with an increased risk of BC which appears to be linked to higher dose and longer duration of treatment [30]. The U.S. Food and Drug Administration (FDA) recommend that healthcare professionals should not prescribe pioglitazone in patients with active BC. Several countries in Europe have removed this agent from the market or included warnings for prescription. Moreover, the benefits of glycaemic control vs. unknown risks for cancer recurrence with pioglitazone should be considered in patients with a prior history of BC. 3.2.6 Bladder schistosomiasis and chronic urinary tract infection Bladder schistosomiasis (bilharzia) is the second most common parasitic infection after malaria, with about 600 million people exposed to infection in Africa, Asia, South America, and the Caribbean [31]. There is a wellestablished relationship between schistosomiasis and urothelial carcinoma (UC) of the bladder, which can progress to squamous cell carcinoma (SCC), however, better control of the disease is decreasing the incidence of SCC of the bladder in endemic zones such as Egypt [32, 33]. Similarly, invasive SCC has been linked to the presence of chronic urinary tract infection (UTI) distinct from schistosomiasis. A direct association between BC and UTIs has been observed in several casecontrol studies, which have reported a two-fold increased risk of BC in patients with recurrent UTIs in some series [34]. However, a recent meta-analysis found no statistical association when pooling data from the most recent and highest quality studies which highlights the need for higher quality data to be able to draw conclusions [35]. Similarly, urinary calculi and chronic irritation or inflammation of the urothelium have been described as possible risk factors for BC. A meta-analysis of case-control and cohort studies suggests a positive association between history of urinary calculi and BC [36]. 3.2.7 Gender Although men are more likely to develop BC than women, women present with more advanced disease and have worse survival rates. A meta-analysis including nearly 28,000 patients shows that female gender was associated with a worse survival outcome (hazard ratio [HR]: 1.20, 95% CI: 1.09–1.32) compared to male gender after radical cystectomy (RC) [37]. This finding had already been presented in a descriptive nationwide analysis based on 27,773 Austrian patients. After their analysis the authors found that cancer-specific survival (CSS) was identical for pT1-tumours in both sexes, while women had a worse CSS in both age cohorts (< 70 years and ≥ 70 years) with higher tumour stages [38]. However, treatment patterns are unlikely to explain the differences in overall survival (OS) [39]. In a population-based study from the Ontario Cancer Registry analysing all patients with BC treated with cystectomy or radical RT between 1994 and 2008, no differences in

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OS, mortality and outcomes were found between males and females following radical therapy [40]. The genderspecific difference in survival for patients with BC was also analysed in the Norwegian population. Survival was inferior for female patients but only within the first 2 years after diagnosis. This discrepancy was partly attributed to a more severe T-stage in female patients at initial diagnoses [41]. A population-based study from the MarketScan databases suggests that a possible reason for worse survival in the female population may be that women experienced longer delays in diagnosis than men, as the differential diagnosis in women includes diseases that are more prevalent than BC [42]. Furthermore, differences in the gender prevalence of BC may be due to other factors besides tobacco and chemical exposure. In a large prospective cohort study, post-menopausal status was associated with an increase in BC risk, even after adjustment for smoking status. This finding suggests that the differences in oestrogen and androgen levels between men and women may be responsible for some of the difference in the gender prevalence of BC [43-45]. Moreover, a recent population study assessing impact of hormones on BC suggests that younger age at menopause (≤ 45 years) is associated with an increased risk of BC [46]. 3.2.8 Genetic factors There is growing evidence that genetic susceptibility factors and family association may influence the incidence of BC. A recent population-based study of cancer risk in relatives and spouses of UC patients showed an increased risk for first- and second-degree relatives, and suggests genetic or environmental roots independent of smoking-related behaviour [47]. Shared environmental exposure was recognised as a potentially confounding factor [48]. Recent studies detected genetic susceptibility with independent loci, which are associated with BC risk [49]. Genome-wide association studies (GWAS) of BC identified several susceptibility loci associated with BC risk [50, 51]. 3.2.9

Summary of evidence and guidelines for epidemiology and risk factors

Summary of evidence Worldwide, bladder cancer is the 10th most commonly diagnosed cancer. Several risk factors associated with bladder cancer diagnosis have been identified. Active and passive tobacco smoking continues to be the main risk factor, while exposure-related incidence is decreasing. The increased risk of developing bladder cancer in patients undergoing external-beam radiotherapy (EBRT), brachytherapy, or a combination of EBRT and brachytherapy, must be considered during patient follow-up. As bladder cancer requires time to develop, patients treated with radiation at a young age are at the greatest risk and should be followed-up closely. Recommendations Council patients to stop active and avoid passive smoking. Inform workers in potentially hazardous workplaces of the potential carcinogenic effects of a number of recognised substances, including duration of exposure and latency periods. Protective measures are recommended. Do not prescribe pioglitazone to patients with active bladder cancer or a history of bladder cancer.

3.3

LE 2a 3 2a 3

Strength rating Strong Strong

Strong

Pathology

3.3.1 Handling of transurethral resection and cystectomy specimens During transurethral resection (TUR), a specimen from the tumour and normal looking bladder wall should be taken, if possible. Specimens should be taken from the superficial and deep areas of the tumour and sent to the pathology laboratory separately, in case the outcome will impact on treatment decisions. If random biopsies of the flat mucosa are taken, each biopsy specimen of the flat mucosa should also be submitted separately [52]. The sampling sites must be recorded by the urologist; the pathologist report should include location of tumour tissue in the cystectomy specimen. Anatomical tumour location is relevant for staging and prognosis [53, 54]. In RC, bladder fixation must be carried out as soon as possible. The pathologist must open the specimen from the urethra to the bladder dome and fix the specimen. In a female cystectomy specimen, the length of the urethral segment removed en bloc with the specimen should be checked, preferably by the urological surgeon [55].

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Specimen handling should follow the general rules as published by a collaborative group of pathologists and urologists [56, 57]. It must be stressed that it may be very difficult to confirm the presence of a neoplastic lesion using gross examination of the cystectomy specimen after TUR or chemotherapy, so the entire retracted or ulcerated area should be included. It is compulsory to study the urethra, the ureters, the prostate in men and the radial margins [58]. In urethra-sparing cystectomy; the level of urethral dissection, completeness of the prostate, specifically at the apex (in men), and the inclusion of the entire bladder neck and amount of adjacent urethra, uterus and vaginal vault (in women) have to be documented by the pathologist. All lymph node (LN) specimens should be provided in their totality, in clearly labelled containers. In case of doubt, or adipose differentiation of the LNs, the entire specimen is to be included. Lymph nodes should be counted and measured on slides; capsular extension and percentage of LN invasion should be reported as well as vascular embols [59, 60]. In case of metastatic spread in the perivesical fat without real LN structures (capsule, subcapsular sinus), this localisation should nevertheless be considered as N+. Potentially positive soft tissue margins should be inked by the pathologist for evaluation [61]. In rare cases, fresh frozen sections may be helpful to determine treatment strategy [62]. 3.3.2 Pathology of muscle-invasive bladder cancer All MIBC cases are high-grade UCs. For this reason, no prognostic information can be provided by grading MIBC [63]. However, identification of morphological subtypes is important for prognostic reasons and treatment decisions [64-66]. The data presented in these guidelines are based on the 2004/2016 World Health Organization (WHO) classifications [67, 68]. Currently the following differentiations are used [64, 69]: 1. urothelial carcinoma (more than 90% of all cases); 2. urothelial carcinomas with partial squamous and/or glandular or trophoblastic differentiation; 3. micropapillary urothelial carcinoma; 4. nested variant (including large nested variant) and microcystic urothelial carcinoma; 5. plasmacytoid, giant cell, signet ring, diffuse, undifferentiated; 6. lymphoepithelioma-like; 7. small-cell carcinomas; 8. sarcomatoid urothelial carcinomas; 9. neuroendocrine variant of urothelial carcinoma; 10. some urothelial carcinomas with other rare differentiations. Outcomes may vary for divergent histologies, which need to be mentioned following international reporting standards [64, 70]. 3.3.3

Guidelines for the assessment of tumour specimens

Recommendations Strength rating Record the depth of invasion (categories pT2a and pT2b, pT3a and pT3b or pT4a and pT4b). Strong Record margins with special attention paid to the radial margin, prostate, ureter, urethra, peritoneal fat, uterus and vaginal vault. Record the total number of lymph nodes (LNs), the number of positive LNs and extranodal spread. Record lymphatic or blood vessel invasion. Record the presence of carcinoma in situ. Record the sampling sites as well as information on tumour size when providing specimens to the pathologist.

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3.3.4

EAU-ESMO consensus statements on the management of advanced- and variant bladder cancer [8, 9]*

Consensus statement Bladder urothelial carcinoma with small cell neuroendocrine variant should be treated with neoadjuvant chemotherapy followed by consolidating local therapy. Muscle-invasive pure squamous cell carcinoma of the bladder should be treated with primary radical cystectomy and lymphadenectomy. Muscle-invasive pure adenocarcinoma of the bladder should be treated with primary radical cystectomy and lymphadenectomy. Muscle-invasive small cell neuroendocrine variant of bladder urothelial carcinoma should not receive preventive brain irradiation to avoid brain recurrence. Differentiating between urachal and non-urachal subtypes of adenocarcinoma is essential when making treatment decisions. *Only statements which met the a priori consensus threshold across all three stakeholder groups are listed (defined as ≥ 70% agreement and ≤ 15% disagreement, or vice versa).

4.

STAGING AND CLASSIFICATION SYSTEMS

4.1

Pathological staging

For staging, the Tumour, Node, Metastasis (TNM) Classification (2017, 8th edition) is recommended [71]. Blood and lymphatic vessel invasion have an independent prognostic significance [72, 73].

4.2

Tumour, node, metastasis classification

The TNM classification of malignant tumours is the method most widely used to classify the extent of cancer spread [71] (Table 4.1). Table 4.1: TNM Classification of urinary bladder cancer [71] T - Primary Tumour Tx Primary tumour cannot be assessed T0 No evidence of primary tumour Ta Non-invasive papillary carcinoma Tis Carcinoma in situ: “flat tumour” T1 Tumour invades subepithelial connective tissue T2 Tumour invades muscle T2a Tumour invades superficial muscle (inner half) T2b Tumour invades deep muscle (outer half) T3 Tumour invades perivesical tissue: T3a microscopically T3b macroscopically (extravesical mass) T4 Tumour invades any of the following: prostate stroma, seminal vesicles, uterus, vagina, pelvic wall, abdominal wall T4a Tumour invades prostate stroma, seminal vesicles, uterus, or vagina T4b Tumour invades pelvic wall or abdominal wall N - Regional Lymph Nodes Nx Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single lymph node in the true pelvis (hypogastric, obturator, external iliac, or presacral) N2 Metastasis in multiple regional lymph nodes in the true pelvis (hypogastric, obturator, external iliac, or presacral) N3 Metastasis in a common iliac lymph node(s)

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M - Distant Metastasis M0 No distant metastasis M1a Non-regional lymph nodes M1b Other distant metastasis Staging after neo-adjuvant chemotherapy (NAC) and radical cystectomy can be done, but must be mentioned as ypTNM (International Collaboration on Cancer Reporting) [70]. ypT0N0 after NAC and cystectomy is associated with good prognosis [74, 75].

5.

DIAGNOSTIC EVALUATION

5.1

Primary diagnosis

5.1.1 Symptoms Painless visible haematuria is the most common presenting complaint. Other presenting symptoms and clinical signs include non-visible haematuria, urgency, dysuria, increased frequency, and in more advanced tumours, pelvic pain and symptoms related to urinary tract obstruction. 5.1.2 Physical examination Physical examination should include rectal and vaginal bimanual palpation. A palpable pelvic mass can be found in patients with locally advanced tumours. In addition, bimanual examination under anaesthesia should be carried out before and after TUR of the bladder (TURB) to assess whether there is a palpable mass or if the tumour is fixed to the pelvic wall [76, 77]. However, considering the discrepancy between bimanual examination and pT stage after cystectomy (11% clinical overstaging and 31% clinical understaging), some caution is suggested with the interpretation of bimanual examination [78]. 5.1.3 Bladder imaging Patients with a bladder mass identified by any diagnostic imaging technique should undergo cystoscopy, biopsy and/or resection for histopathological diagnosis and staging. The high specificity of diagnostic imaging for detecting bladder cancer means that patients with imaging positive for bladder cancer may avoid diagnostic flexible cystoscopy and go directly to rigid cystoscopy and transurethral resection [79, 80]. 5.1.4 Urinary cytology Examination of voided urine or bladder washings for exfoliated cancer cells has high sensitivity in high-grade tumours and is a useful indicator in cases of high-grade malignancy or CIS. However, positive urinary cytology may originate from a urothelial tumour located anywhere in the urinary tract. Evaluation of cytology specimens can be hampered by low cellular yield, UTIs, stones or intravesical instillations, but for experienced readers, specificity exceeds 90% [81, 82]. However, negative cytology does not exclude a tumour. There is no known urinary marker specific for the diagnosis of invasive BC [83]. A standardised reporting system, the ‘Paris System’ redefining urinary cytology diagnostic categories was published in 2016 [84]: • adequacy of urine specimens (Adequacy); • negative for high-grade UC (Negative); • atypical urothelial cells (AUC); • suspicious for high-grade UC (Suspicious); • high-grade UC (HGUC); • low-grade urothelial neoplasia (LGUN). 5.1.5 Cystoscopy Ultimately, the diagnosis of BC is made by cystoscopy and histological evaluation of resected tissue. An (outpatient) flexible cystoscopy is recommended to obtain a complete image of the bladder. However, in daily practice, If a bladder tumour has been visualised unequivocally by imaging studies such as computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound (US), diagnostic cystoscopy may be omitted and the patient can proceed directly to TURB for histological diagnosis and resection. During the procedure, a thorough investigation of the bladder with rigid cystoscopy under anaesthesia is mandatory in order not to miss any tumours at the level of the bladder neck.

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Currently, there is no evidence for the role of photodynamic diagnosis (PDD) in the standard diagnosis of invasive BC. A careful description of the cystoscopic findings is necessary. This should include documentation of the site, size, number, and appearance (papillary or solid) of the tumours, as well as a description of any mucosal abnormalities [85]. The use of a bladder diagram is recommended. The use of PDD could be considered if a T1 high-grade tumour is present and to identify associated CIS. Presence of CIS may lead to a modified treatment plan (see EAU Guidelines on Non-muscle-invasive Bladder Cancer [2]). Photodynamic diagnosis is highly sensitive for the detection of CIS and in experienced hands the rate of false-positive results may be similar to that with regular white-light cystoscopy [73, 86]. 5.1.6 Transurethral resection of invasive bladder tumours The goal of TURB is to enable histopathological diagnosis and staging, which requires the inclusion of bladder muscle in the resection specimen. In case MIBC is suspected, tumours need to be resected separately in parts, which include the exophytic part of the tumour, the underlying bladder wall with the detrusor muscle, and the edges of the resection area. At least the deeper part of the resection specimen must be referred to the pathologist in a separate labelled container to enable making a correct diagnosis. In cases in which RT is considered and CIS is to be excluded, PDD can be used [87]. The involvement of the prostatic urethra and ducts in men with bladder tumours has been reported. The exact risk is not known, but it seems to be higher if the tumour is located on the trigone or bladder neck, with concomitant bladder CIS, and in the case of multiple tumours [54, 88, 89]. Involvement of the prostatic urethra can be determined either at the time of primary TURB or by frozen section during the cystoprostatectomy procedure. A frozen section has a higher negative-predictive value and is more accurate [90-92]. A negative urethral frozen section can reliably identify patients in whom urethrectomy should be avoided. However, a positive pre-operative biopsy seems to have limited utility as these findings are not reliably associated with final margin status [90, 93]. Diagnosis of a urethral tumour before cystectomy will result in a urethrectomy which could be a contraindication for an orthotopic diversion. However, an orthotopic diversion should not be denied based on positive pre-operative biopsy findings alone and frozen section should be part of the radical cystectomy procedure, in particular in male patients [94, 95]. 5.1.7 Concomitant prostate cancer Prostate cancer is found in 21–50% of male patients undergoing RC for BC [96-99]. Incidentally discovered clinically significant prostatic adenocarcinoma did not alter survival [98, 99]. Pathological reporting of the specimens should follow the recommendations as presented in the EAU-EANM-ESTRO-ESUR-SIOG Guidelines on Prostate Cancer [100]. 5.1.8

Summary of evidence and guidelines for the primary assessment of presumably invasive bladder tumours

Summary of evidence Cystoscopy is necessary for the diagnosis of bladder cancer. Urinary cytology has high sensitivity in high-grade tumours including carcinoma in situ. In men, prostatic urethral biopsy includes resection from the bladder neck to the verumontanum (between the 5 and 7 o’clock position) using a resection loop. In case any abnormal-looking areas in the prostatic urethra are present at this time, these need to be biopsied as well.

Recommendations Describe all macroscopic features of the tumour (site, size, number and appearance) and mucosal abnormalities during cystoscopy. Use a bladder diagram. Take a biopsy of the prostatic urethra in cases of bladder neck tumour, when bladder carcinoma in situ is present or suspected, when there is positive cytology without evidence of tumour in the bladder, or when abnormalities of the prostatic urethra are visible. In men with a negative prostatic urethral biopsy undergoing subsequent orthotopic neobladder construction an intra-operative frozen section can be omitted.

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LE 1 2b 2b

Strength rating Strong Strong

Strong

17

Strong In men with a prior positive transurethral prostatic biopsy, subsequent orthotopic neobladder construction should not be denied a priori, unless an intra-operative frozen section of the distal urethral stump reveals malignancy at the level of urethral dissection. Strong In women undergoing subsequent orthotopic neobladder construction, obtain procedural information (including histological evaluation) of the bladder neck and urethral margin, either prior to, or at the time of cystectomy. In the pathology report, specify the grade, depth of tumour invasion, and whether the Strong lamina propria and muscle tissue are present in the specimen. (For general information on the assessment of bladder tumours, see EAU Guidelines on Non-muscle-invasive Bladder Cancer [2]). 5.1.9

EAU-ESMO consensus statements on the management of advanced- and variant bladder cancer [8, 9]*

Consensus statement Differentiating between urachal and non-urachal subtypes of adenocarcinoma is essential when making treatment decisions. *Only statements which met the a priori consensus threshold across all three stakeholder groups are listed (defined as ≥ 70% agreement and ≤ 15% disagreement, or vice versa).

5.2

Imaging for staging of MIBC

In clinical practice, tumour stage and histopathological grade are used to guide treatment and determine prognosis [69, 101, 102]. Computed tomography and MRI are the imaging techniques most commonly used for tumour staging. If the correct choice of treatment is to be made, staging must be accurate. The goal of imaging patients with bladder cancer is to determine: • extent of local tumour invasion, ideally differentiating T1 from T2 tumours as the treatment is different; • tumour spread to LNs; • tumour spread to the upper UT and other distant organs (e.g., liver, lungs, bones, peritoneum, pleura, and adrenal glands). 5.2.1 Local staging of MIBC Multiparametric MRI (mpMRI) using the Vesical Imaging Reporting and Data System (VI-RADS) scoring system may differentiate between muscle- and non-muscle-invasive primary BC with high diagnostic accuracy. A recent meta-analysis found that the pooled sensitivity and specificity of mpMRI with VI-RADS acquisition and scoring for predicting MIBC were 0.83 and 0.90, respectively. This diagnostic performance of VI-RADS is similar to the diagnostic performance of bladder MRI in determining MIBC prior to the introduction of VI-RADS based on a previous meta-analysis of 24 studies in which the pooled sensitivity and specificity were 0.92 (95% CI: 0.88–0.95) and 0.87 (95% CI: 0.78–0.93), respectively [103]. The Vesical Imaging Reporting and Data System offers a standardised approach to both acquisition and reporting of mpMRI for BC. How mpMRI is best used in clinical practice and which cut off levels to use for VI-RADS scoring is still to be determined [103]. Magnetic resonance imaging has superior soft tissue contrast resolution compared with CT. The accuracy of MRI for primary tumour staging varies from 73% to 96% (mean 85%). A meta-analysis of 17 studies showed a 91% sensitivity and 96% specificity for 3.0-T device MRI combined with diffusion-weighted imaging (DWI) to differentiate ≤ T1 tumours from ≥ T2 tumours before surgery [104]. Both CT and MRI may be used for assessment of local invasion by T3b disease, or higher, but they are unable to accurately diagnose microscopic invasion of perivesical fat (T2 vs. T3a) [105]. Magnetic resonance imaging may evaluate post-biopsy reaction because enhancement of the tumour occurs earlier than that of the normal bladder wall due to neovascularisation [106, 107]. In 2006, a link was established between the use of gadolinium-based contrast agents and nephrogenic systemic fibrosis (NSF), which may result in fatal or severely debilitating systemic fibrosis. Patients with impaired renal function are at risk of developing NSF and non-ionic linear gadolinium-based contrast agents should be avoided (gadodiamide, gadopentetate dimeglumine and gadoversetamide). A stable macrocyclic contrast agent should be used (gadobutrol, gadoterate meglumine or gadoteridol). Contrast-enhanced CT using iodinated contrast media can be considered as an alternative [108].

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5.2.1.1 CT imaging for local staging of MIBC The advantages of CT include high spatial resolution, shorter acquisition time, wider coverage in a single breath hold, and lower susceptibility to variable patient factors. Computed tomography is unable to differentiate between stages Ta to T3a tumours, but it is useful for detecting invasion into the perivesical fat (T3b) and adjacent organs. The accuracy of CT in determining extravesical tumour extension varies from 55% to 92% [109] and increases with more advanced disease [110]. 5.2.2 Imaging of lymph nodes in MIBC Assessment of LN metastases based solely on size is limited by the inability of both CT and MRI to identify metastases in normal-sized or minimally-enlarged nodes. The sensitivity for detection of LN metastases is low (48–87%). Specificity is also low because nodal enlargement may be due to benign disease. Overall, CT and MRI show similar results in the detection of LN metastases in a variety of primary pelvic tumours [111-115]. Pelvic nodes > 8 mm and abdominal nodes > 10 mm in maximum short-axis diameter, detected by CT or MRI, should be regarded as pathologically enlarged [116, 117]. Positron emission tomography (PET) combined with CT is increasingly being used in clinical practice and its exact role continues to be evaluated [118]. 5.2.3 Upper urinary tract urothelial carcinoma 5.2.3.1 Computed tomography urography Computed tomography urography has the highest diagnostic accuracy of the available imaging techniques [119]. The sensitivity of CT urography for UTUC is 0.67–1.0 and specificity is 0.93–0.99 [120]. Rapid acquisition of thin sections allows high-resolution isotropic images that can be viewed in multiple planes to assist with diagnosis without loss of resolution. Epithelial “flat lesions” without mass effect or urothelial thickening are generally not visible with CT. The secondary sign of hydronephrosis is associated with advanced disease and poor oncological outcome [121, 122]. The presence of enlarged LNs is highly predictive of metastases in UTUC [123]. 5.2.3.2 Magnetic resonance urography Magnetic resonance urography is indicated in patients who cannot undergo CT urography, usually when radiation or iodinated contrast media are contraindicated [124]. The sensitivity of MR urography is 0.75 after contrast injection for tumours < 2 cm [124]. The use of MR urography with gadolinium-based contrast media should be limited in patients with severe renal impairment (< 30 mL/min creatinine clearance), due to the risk of NSF. Computed tomography urography is generally preferred to MR urography for diagnosing and staging UTUC. 5.2.4 Distant metastases at sites other than lymph nodes Prior to any curative treatment, it is essential to evaluate the presence of distant metastases. Computed tomography and MRI are the diagnostic techniques of choice to detect lung [125] and liver metastases [126], respectively. Bone and brain metastases are rare at the time of presentation of invasive BC. A bone scan and additional brain imaging are therefore not routinely indicated unless the patient has specific symptoms or signs to suggest bone or brain metastases [127, 128]. Magnetic resonance imaging is more sensitive and specific for diagnosing bone metastases than bone scintigraphy [129, 130]. 5.2.5 Future developments Evidence is accruing in the literature suggesting that 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT might have potential clinical use for staging metastatic BC [131, 132], but there is no consensus as yet. The results of further trials are awaited before a recommendation can be made. Recently, the first study was published showing the superior feasibility of DWI over T2-weighted and dynamic contrastenhanced (DCE)-MRI in assessing the therapeutic response to induction chemotherapy against MIBC [133]. The high specificity of DWI indicates that it is useful for accurate prediction of a complete histopathological response, allowing better patient selection for bladder-sparing protocols. Results from prospective studies are awaited.

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5.2.6

Summary of evidence and guidelines for staging in muscle-invasive bladder cancer

Summary of evidence LE Imaging as part of staging in muscle-invasive bladder cancer (MIBC) provides information about 2b prognosis and assists in selection of the most appropriate treatment. There are currently insufficient data on the use of diffusion-weighted imaging (DWI) and 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in MIBC to allow for a recommendation to be made. The diagnosis of upper tract urothelial carcinoma depends on CT urography and ureteroscopy. 2

Recommendations In patients with confirmed muscle-invasive bladder cancer, use computed tomography (CT) of the chest, abdomen and pelvis for staging, including some form of CT urography with designated phases for optimal urothelial evaluation. Use magnetic resonance urography when CT urography is contraindicated for reasons related to contrast administration or radiation dose. Use CT or magnetic resonance imaging (MRI) for staging locally advanced or metastatic disease in patients in whom radical treatment is considered. Use CT to diagnose pulmonary metastases. Computed tomography and MRI are generally equivalent for diagnosing local disease and distant metastases in the abdomen.

5.3

Strength rating Strong

Strong Strong Strong

MIBC and health status

Complications from RC may be directly related to pre-existing comorbidity as well as the surgical procedure, bowel anastomosis, or urinary diversion. A significant body of literature has evaluated the usefulness of age as a prognostic factor for RC, although chronological age is less important than frailty [134-136]. Frailty is a syndrome of reduced ability to respond to stressors. Patients with frailty have a higher risk of mortality and negative side effects of cancer treatment [137]. Controversy remains regarding age, RC and the type of urinary diversion. Radical cystectomy is associated with the greatest risk reduction in disease-related and nondisease-related death in patients aged < 80 years [138]. The largest retrospective study on RC in septuagenarians and octogenarians based on data from the National Surgical Quality Improvement Program database (n = 1,710) showed no significant difference for wound, cardiac, or pulmonary complications. However, the risk of mortality in octogenarians compared to septuagenarians is higher (4.3% vs. 2.3%) [139]. Although some octogenarians successfully underwent a neobladder procedure, most patients were treated with an ileal conduit diversion. It is important to evaluate functioning and quality of life (QoL) of older patients using a standardised geriatric assessment, as well as carrying out a standard medical evaluation [140]. Sarcopenia has been shown to be an independent predictor for OS and CSS in a large multicentre study with patients undergoing RC for BC [141]. In order to predict CSM after RC in patients receiving neoadjuvant chemotherapy (NAC), sarcopenia should be assessed after completing the chemotherapy [142]. Other risk factors for morbidity include prior abdominal surgery, extravesical disease, and prior RT [143]. Female gender, an increased BMI and lower pre-operative albumin levels are associated with a higher rate of parastomal hernias [144]. Low pre-operative serum albumin is also associated with impaired wound healing, gastrointestinal (GI) complications and a decrease of recurrence-free and OS after RC [145, 146]. Therefore, it could be used as a prognostic biomarker for patients undergoing RC. 5.3.1 Evaluation of comorbidity, frailty and cognition Rochon et al. have shown that evaluation of comorbidity provides a better indicator of life expectancy in MIBC than patient age [147]. Evaluation of comorbidity helps to identify factors likely to interfere with, or have an impact on, treatment and the evolution and prognosis of MIBC [148]. The value of assessing overall health before recommending and proceeding with surgery was emphasised by Zietman et al., who have demonstrated an association between comorbidity and adverse pathological and survival outcomes following RC [149]. Similar results were found for the impact of comorbidity on cancer-specific and other-cause mortality in a population-based competing risk analysis of > 11,260 patients from the Surveillance, Epidemiology, and End Results (SEER) registries. Age carried the highest risk for other-cause mortality but not for increased cancer-specific death, while the stage of locally advanced tumour was the strongest predictor for decreased CSS [150]. Stratifying older patients according to frailty using a multidisciplinary approach will help select

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patients most likely to benefit from radical surgery and to optimise treatment outcomes [151]. There are many different screening tools available for frailty and local approaches can be used. Examples include the G8 and the Clinical Frailty Scale (See Table 5.1 and Figure 5.1 below). Cognitive impairment can be screened for using a tool such as the mini-COG (https://mini-cog. com/), which consists of three-word recall and a clock-drawing test, and can be completed within 5 minutes. A score of ≤ 3/5 indicates the need to refer the patient for full cognitive assessment. Patients with any form of cognitive impairment (e.g., Alzheimer’s or vascular dementia) may need a capacity assessment of their ability to make an informed decision, which is an important factor in health status assessment. Cognitive impairment also predicts risk of delirium, which is important for patients undergoing surgery [152]. Table 5.1: G8 screening tool (adapted from [153])

A

B

C

D

E

F G

H

Items Has food intake declined over the past 3 months due to loss of appetite, digestive problems, chewing, or swallowing difficulties?

Possible responses (score) 0 = severe decrease in food intake 1 = moderate decrease in food intake 2 = no decrease in food intake Weight loss during the last 3 months? 0 = weight loss > 3 kg 1 = does not know 2 = weight loss between 1 and 3 kg 3 = no weight loss Mobility? 0 = bed or chair bound 1 = able to get out of bed/chair but does not go out 2 = goes out Neuropsychological problems? 0 = severe dementia or depression 1 = mild dementia 2 = no psychological problems 0 = BMI < 19 BMI? (weight in kg)/(height in m2) 1 = BMI 19 to < 21 2 = BMI 21 to < 23 3 = BMI ≥ 23 Takes more than three prescription drugs per day? 0 = yes 1 = no 0.0 = not as good In comparison with other people of the same age, how does the patient consider his/her health 0.5 = does not know status? 1.0 = as good 2.0 = better Age 0 = ≥ 85 1 = 80–85 2 = < 80 Total score 0–17

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21

Figure 5.1: Clinical Frailty Scale©, Version 2.0* [154]

CLINICAL FRAILTY SCALE

1 2

LIVING WITH MODERATE FRAILTY

People who need help with all outside activities and with keeping house. Inside, they often have problems with stairs and need help with bathing and might need minimal assistance (cuing, standby) with dressing.

7

LIVING WITH SEVERE FRAILTY

Completely dependent for personal care, from whatever cause (physical or cognitive). Even so, they seem stable and not at high risk of dying (within ~6 months).

8

LIVING WITH VERY SEVERE FRAILTY

VERY People who are robust, active, energetic FIT and motivated. They tend to exercise regularly and are among the fittest for their age.

FIT People who have no active disease

symptoms but are less fit than category 1. Often, they exercise or are very active occasionally, e.g., seasonally.

3

MANAGING People whose medical problems are WELL well controlled, even if occasionally

4

LIVING WITH VERY MILD FRAILTY

5

6

symptomatic, but often are not regularly active beyond routine walking.

LIVING WITH MILD FRAILTY

Previously “vulnerable,” this category marks early transition from complete independence. While not dependent on others for daily help, often symptoms limit activities. A common complaint is being “slowed up” and/or being tired during the day. People who often have more evident slowing, and need help with high order instrumental activities of daily living (finances, transportation, heavy housework). Typically, mild frailty progressively impairs shopping and walking outside alone, meal preparation, medications and begins to restrict light housework.

9

Completely dependent for personal care and approaching end of life. Typically, they could not recover even from a minor illness.

TERMINALLY Approaching the end of life. This ILL category applies to people with a life expectancy 90 years Metastatic solid tumours AIDS

Interpretation: 1. Calculate Charlson Comorbidity Score or Index = i a. Add comorbidity score to age score b. Total denoted as ‘i’ in the Charlson Probability calculation (see below). i = sum of comorbidity score to age score 2. Calculate Charlson Probability (10-year mortality = Y) a. Calculate Y = 10(i x 0.9) b. Calculate Z = 0.983Y (where Z is the 10-year survival) 5.3.3

Summary of evidence and guidelines for comorbidity scales

Summary of evidence Chronological age is of limited relevance. It is important to screen for frailty and cognitive impairment and provide a Comprehensive Geriatric Assessment (CGA) where optimisation is needed.

Recommendations Base the decision on bladder-sparing treatment or radical cystectomy in older/frail patients with invasive bladder cancer on tumour stage and frailty. Assess comorbidity by a validated score, such as the Charlson Comorbidity Index. The American Society of Anesthesiologists score should not be used in this setting (see Section 5.3.2).

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LE 3 3

Strength rating Strong Strong

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6.

MARKERS

6.1

Introduction

Both patient and tumour characteristics guide treatment decisions and prognosis of patients with MIBC.

6.2

Prognostic markers

6.2.1 Histopathological and clinical markers The most important histopathological prognostic variables after RC and LN dissection are tumour stage and LN status [179]. In addition, other histopathological parameters of the RC specimen have been associated with prognosis. The value of lymphovascular invasion was reported in a systematic review and meta-analysis including 78,000 patients from 65 studies treated with RC for BC [180]. Lymphovascular invasion was present in 35% of the patients and correlated with a 1.5-fold higher risk of recurrence and CSM, independent of pathological stage and peri-operative chemotherapy. This correlation was even stronger in those patients with node-negative disease [181]. In a systematic review and meta-analysis including 23 studies and over 20,000 patients, the presence of concomitant CIS in the RC specimen was associated with a higher odds ratio (OR) of ureteral involvement (pooled OR: 4.51, 2.59–7.84). Concomitant CIS was not independently associated with OS, recurrence-free survival (RFS) and DSS in all patients, but in patients with organ-confined disease concomitant CIS was associated with worse RFS (pooled HR: 1.57, 1.12–2.21) and CSM (pooled HR: 1.51, 1.001–2.280) [181]. Tumour location has been associated with prognosis. Tumours located at the bladder neck or trigone of the bladder appear to have an increased likelihood of nodal metastasis (OR: 1.83, 95% CI: 1.11–2.99) and have been associated with decreased survival [179, 182-184]. Prostatic urethral involvement at the time of RC was also found to be associated with worse survival outcomes. In a series of 995 patients, prostatic involvement was recorded in 31% of patients. The 5-year CSS in patients with CIS of the prostatic urethra was 40%, whilst the prognosis of patients with UC invading the prostatic stroma was worse with a 5-year CSS of only 12% [185]. Neutrophil-to-lymphocyte ratio (NLR) has emerged as a prognostic factor in UUT tumours [1] and other non-urological malignancies. In a pooled analysis of 21 studies analysing the prognostic role of NLR in BC, the authors correlated elevated pre-treatment NLR with OS, RFS and disease-free survival (DFS) in both localised and metastatic disease [186]. In contrast, a secondary analysis of the Southwest Oncology Group (SWOG) 8710 trial, a randomised phase III trial assessing cystectomy ± NAC in patients with MIBC, suggests that NLR is neither a prognostic nor a predictive biomarker for OS in MIBCs [187]. In patients with LN-positive disease, the American Joint Committee on Cancer (AJCC)-TNM staging system provides 3 subcategories. In addition, several other prognostic LN-related parameters have been reported. These include, but are not limited to, the number of positive LNs, the number of LNs removed, LN density (the ratio of positive LNs to the number of LNs removed) and extranodal extension. In a systematic review and meta-analysis, it was reported that LN density was independently associated with OS (HR: 1.45, 95%, CI: 1.11–1.90) [188]. It has been suggested that LN density outperforms the AJCC-TNM staging system for LN-positive disease in terms of prognostic value [189]. However, in spite of these studies supporting the use of LN density, LN density relies on the number of LNs removed which, in turn, is subject to surgical and pathological factors. This makes the concept of LN density difficult to apply uniformly [190]. Two studies investigated whether any of the reported LN-related parameters may be superior to the routinely used AJCC-TNM staging system [190, 191]. Whilst the conclusion was that the AJCC-TNM staging system for LN status did not perform well, none of the other tested variables outperformed the AJCC system. 6.2.2 Molecular markers 6.2.2.1 Molecular subtypes based on the Cancer Genome Atlas cohort The updated Cancer Genome Atlas (TCGA) reported on 412 MIBCs and identified two main groups; luminal and basal-squamous - consisting of five mRNA expression-based molecular subtypes including luminalpapillary, luminal-infiltrated, luminal; basal-squamous; and neuronal, a subtype associated with poor survival in which the majority of tumours do not have small cell or neuroendocrine histology. Each subtype is associated with distinct mutational profiles, histopathological features and prognostic and treatment implications [192]. The basal-squamous subtype is characterised by expression of basal keratin markers, immune infiltrates and is felt to be chemo sensitive. The different luminal subtypes are characterised by fibroblast growth factor receptor 3 (FGFR3) alterations (luminal-papillary), epithelial-mesenchymal transition (EMT) markers (luminal-infiltrated) and may be associated with chemotherapy resistance [65, 66, 192, 193].

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In 2019, a consensus on molecular subtype classification was reported [194]. The authors analysed 1,750 MIBC transcriptomic profiles from 18 datasets and identified six MIBC molecular classes that reconcile all previously published classification schemes. The molecular subgroup classes include luminal papillary (LumP), luminal non-specified (LumNS), luminal unstable (LumU), stroma-rich, basal/squamous (Ba/Sq), and neuroendocrine-like (NE-like). Each class has distinct differentiation patterns, oncogenic mechanisms, tumour micro-environments and histological and clinical associations. However, the authors stressed that consensus was reached for biological rather than clinical classes. Therefore, at this time, the classification should be considered as a research tool for retrospective and prospective studies until future studies establish how these molecular subgroups can be used best in a clinical setting. Molecular classification of MIBC is still evolving and treatment tailored to molecular subtype is not a standard yet. A novel 12-gene signature derived from patients in the TCGA utilising published gene signatures has been developed and externally validated to predict OS in MIBC [195]. Interestingly, a recently published analysis of molecular subtyping in MIBC demonstrated that although molecular subtypes reflect the heterogeneity of bladder tumours and are associated with tumour grade, clinical parameters outperformed subtypes for predicting outcome [196]. In the coming years, new insights into BC carcinogenesis may change our management of the disease and our ability to better predict outcomes.

6.3

Predictive markers

6.3.1 Clinical and histopathological markers Based on retrospective data only, patients with secondary MIBC have a worse response to NAC compared to patients with primary MIBC [197]. Pietzak et al. retrospectively analysed clinico-pathologic outcomes comparing 245 patients with clinical T2–4a N0M0 primary MIBC and 43 patients with secondary MIBC treated with NAC and RC. They found that patients with secondary MIBC had lower pathologic response rates following NAC than those with primary MIBC (univariable 26% vs. 45%, multivariable OR: 0.4 [95% CI: 0.18–0.84, p = 0.02]). They also found that MIBC patients progressing after NAC had worse CSS as compared to patients treated with cystectomy alone (p = 0.002). Variant histologies and non-UC have also been linked to worse outcomes after NAC, but there is, as yet, insufficient data to conclude that they can be considered as predictive markers [198]. 6.3.2 Molecular markers Several predictive biomarkers have been investigated such as serum vascular endothelial growth factor [199], circulating tumour cells as well as defects in DNA damage repair (DDR) genes including ERCC2, ATM, RB1 and FANCC that may predict response to cisplatin-based NAC [200, 201]. More recently, alterations in FGFR3 including both mutations and gene fusions have been shown to be associated with response to FGFR inhibitors [202, 203]. More recent efforts have focused on markers for predicting response to immune checkpoint inhibition. Programmed death-ligand 1 (PD-L1) expression by immunohistochemistry has been evaluated in several studies with mixed results which may in part be related to the use of different antibodies and various scoring systems evaluating different compartments i.e., tumour cells, immune cells, or both. The major limitation of PD-L1 staining relates to the significant proportion of PD-L1-negative patients that respond to immune checkpoint blockade. For example, in the IMvigor 210 phase II study of atezolizumab in patients with advanced/metastatic UC who progressed after platinum-based chemotherapy, responses were seen in 18% of patients with low/ no PD-L1 expression [204]. At present, the only indication for PD-L1 testing relates to the use of immune checkpoint inhibitors as monotherapy in patients with locally advanced or metastatic UC unfit for cisplatincontaining chemotherapy who have not received prior therapy. In this setting, pembrolizumab or atezolizumab should only be used in patients unfit for cisplatin-containing chemotherapy whose tumours overexpress PD-L1 (i.e., Combined Positive Score [CPS] ≥ 10 using the 22C3 assay for pembrolizumab and tumour-infiltrating immune cells [IC] covering ≥ 5% of the tumour area using the SP142 assay for atezolizumab) [205]. Urothelial cancer is associated with a high tumour mutational burden (TMB) [206]. Both predicted neoantigen burden and tumour mutational burden have been associated with response to immune checkpoint blockade in several malignancies. High TMB has been associated with response to immune checkpoint inhibitors in metastatic BC [204, 207]. Conflicting results have been seen in studies evaluating immune checkpoint inhibitors in the neoadjuvant setting with the Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE)-01 study utilising pembrolizumab demonstrating an association of high TMB with response while there was no association with atezolizumab in the Phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in MIBC (ABACUS) [208, 209].

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Other markers that have been evaluated in predicting response to immune checkpoint inhibitors include molecular subtypes as discussed earlier, CD8 expression by immunohistochemistry and other immune gene cell signatures. Recent work has focused on the importance of stroma including the role of TGFß in predicting response to immune checkpoint blockade [210, 211]. Although promising, there are currently no validated predictive molecular markers that are routinely used in clinical practice. Further validation studies are awaited.

6.4

Conclusion

The updated Cancer Genome Atlas and other efforts have refined our understanding of the molecular underpinnings of bladder cancer biology. Molecular subtypes, immune gene signatures as well as stromal signatures may ultimately have an important role in predicting response to immunotherapy. Although PD-L1 expression by immunohistochemistry and TMB have demonstrated predictive value in certain settings, additional studies are needed. Prospectively validated prognostic and predictive molecular biomarkers will present valuable adjuncts to clinical and pathological data, but large phase III randomised controlled trials (RCTs) with long-term follow-up will be needed to clarify the many questions remaining.

6.5

Summary of evidence and recommendations for urothelial markers

Summary of evidence There is insufficient evidence to use TMB, molecular subtypes, immune or other gene expression signatures for the management of patients with urothelial cancer.

Recommendations Evaluate PD-L1 expression (by immunohistochemistry) to determine the potential for use of pembrolizumab or atezolizumab in previously untreated patients with locally advanced or metastatic urothelial cancer who are unfit for cisplatin-based chemotherapy. Evaluate for FGFR2/3 genetic alterations for the potential use of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma who have progressed following platinum-containing chemotherapy (including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy).

7.

DISEASE MANAGEMENT

7.1

Neoadjuvant therapy

LE -

Strength rating Weak

Weak

7.1.1 Introduction The standard treatment for patients with urothelial MIBC and MIBC with variant histologies is RC. However, RC only provides 5-year survival in about 50% of patients [212-216]. To improve these results in patients with cN0M0 disease, cisplatin-based NAC has been used since the 1980s [212-218]. 7.1.2 Role of cisplatin-based chemotherapy There are theoretical advantages and disadvantages of administering chemotherapy before planned definitive surgery to patients with resectable muscle-invasive UC of the bladder and cN0M0 disease: • Chemotherapy is delivered at the earliest time-point, when the burden of micrometastatic disease is expected to be low. • Potential reflection of in-vivo chemosensitivity. • Tolerability of chemotherapy and patient compliance are expected to be better pre-cystectomy. • Patients may respond to NAC and have a favourable pathological response as determined mainly by achieving ypT0, ≤ ypT1, ypN0 and negative surgical margins. • Delayed cystectomy might compromise the outcome in patients not sensitive to chemotherapy [219221]. However, there are no prospective trials indicating that delayed surgery due to NAC has a negative impact on survival. In the recently reported French Genito-Urinary Group and the French Association of Urology (GETUG/AFU) V05 Randomized Phase III VESPER trial, comparing gemcitabine/cisplatin (GC) vs. high-dose-intensity methotrexate, vinblastine, doxorubicine and cisplatin (HD-MVAC) in the peri-operative setting, approximately 90% of patients proceeded to surgery after neoadjuvant dose-dense MVAC (ddMVAC) or GC (median delay of surgery was 48 days for GC and 51 days for ddMVAC) [222].

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•

• • •

Neoadjuvant chemotherapy does not seem to affect the outcome of surgical morbidity. In one randomised trial the same distribution of grade 3–4 post-operative complications was seen in both treatment arms [223]. In the combined Nordic trials (n = 620), NAC did not have a major adverse effect on the percentage of performable cystectomies. The cystectomy frequency was 86% in the experimental arm and 87% in the control arm with 71% of patients receiving all three chemotherapy cycles [224]. Clinical staging using bimanual palpation, CT or MRI may result in over- and understaging and have a staging accuracy of only 70% [78]. Overtreatment is a possible negative consequence. Gender may have an impact on chemotherapeutic response and oncologic outcomes [225, 226]. Neoadjuvant chemotherapy should only be used in patients eligible for cisplatin-combination chemotherapy; other combinations (or monotherapies) are inferior in metastatic BC and have not been fully tested in a neoadjuvant setting [223, 227-235].

7.1.2.1 Summary of available data Several randomised phase III trials addressed the potential survival benefit of NAC administration [223, 227232, 236-240]. The main differences in trial designs were the type of chemotherapy (i.e., single-agent cisplatin or combination chemotherapy) and the number of cycles provided. Patients had to be fit for cisplatin. Since these studies differed considerably for patient numbers, patient characteristics (e.g., clinical T-stages included) and the type of definitive treatment offered (cystectomy and/or RT), pooling of results was not possible. Three meta-analyses were undertaken to establish if NAC prolongs survival [233-235]. In a meta-analysis, published in 2005 [235] with updated patient data from 11 randomised trials (n = 3,005), a significant survival benefit was shown in favour of NAC. The most recent meta-analysis included four additional randomised trials, and used the updated results from the Nordic I, Nordic II, and BA06 30894 trials including data from 427 new patients and updated information from 1,596 patients. The results of this analysis confirmed the previously published data and showed an 8% absolute improvement in survival at five years with a number needed-to-treat of 12.5 [241]. Only cisplatin-combination chemotherapy with at least one additional chemotherapeutic agent resulted in a meaningful therapeutic benefit [233, 235]; the regimens tested were methotrexate, vinblastine, adriamycin (epirubicin) plus cisplatin (MVA(E)C), cisplatin, methotrexate plus vinblastine (CMV), cisplatin plus methotrexate (CM), cisplatin plus adriamycin and cisplatin plus 5-fluorouracil (5-FU) [242]. The updated analysis of a large phase III RCT [227] with a median follow-up of eight years confirmed previous results and provided additional findings: • 16% reduction in mortality risk; • improvement in 10-year survival from 30% to 36% with neoadjuvant CMV; • benefit with regard to distant metastases; • the addition of neoadjuvant CMV provided no benefit for locoregional control and locoregional DFS, independent of the definitive treatment. More modern chemotherapeutic regimens such as GC have shown similar pT0/pT1 rates as methotrexate, vinblastine, adriamycin plus cisplatin in retrospective series and pooled data analyses [242-245]. Modified ddMVAC was tested in two small single-arm phase II studies demonstrating high rates of pathologic complete remission [246, 247]. Moreover, a large cross-sectional analysis showed higher rates of down-staging and pathological complete response for ddMVAC [248]. The recently reported results from the GETUG/AFU V05 VESPER randomised trial of ddMVAC vs. gemcitabine and cisplatin as peri-operative chemotherapy in patients with MIBC demonstrated similar pathologic response rates (ypT0N0) in patients treated with neoadjuvant ddMVAC or GC of 42% and 36%, respectively (p = 0.2). An organ-confined status (< ypT3pN0) was obtained in 154 (77%) and 124 (63%) patients, respectively (p = 0.001). Dose-dense MVAC was associated with more severe asthenia and gastrointestinal side effects than GC. Although a higher local control rate (complete pathological response, tumour down-staging, or organ confined) was observed in the ddMVAC arm (p = 0.021), the primary endpoint of PFS at three years is not yet mature [222]. Another dose-dense regimen using cisplatin/ gemcitabine was reported in two small phase II trials [249, 250]. While pathological response rates (< pT2) in the range of 45%–57% were achieved, one trial had to be closed prematurely due to high rates of severe vascular events [249]. This approach is therefore not recommended outside of clinical trials. As an alternative to the standard dose of cisplatin-based NAC with 70 mg/m2 on day 1, split-dose modifications regimens are often used with 35 mg/m2 on days 1+8 or days 1+2. In a retrospective analysis the standard schedule was compared to a split-dose schedule in terms of complete and partial pathological response. A lower number of complete and partial response rates was seen in the split-dose group, but these results were not statistically significant [251].

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There seem to be differences in the outcomes of patients treated with NAC for primary or secondary MIBC. However, in the absence of prospective data, patients with secondary MIBC should be treated similarly to those presenting with primary MIBC [197]. It is unclear, if patients with non-UC histology will also benefit from NAC. A retrospective analysis demonstrated that patients with neuroendocrine tumours had improved OS and lower rates of non-organ-confined disease when receiving NAC. In case of micropapillary differentiation, sarcomatoid differentiation and adenocarcinoma, lower rates of non-organ confined disease were found, but no statistically significant impact on OS. Patients with SCC did not benefit from NAC [252]. A retrospective analysis assessed the use of NAC in MIBC based on data from the U.S. National Cancer Database [253]. Only 19% of all patients received NAC before RC (1,619 of 8,732 patients) and no clear survival advantage for NAC following propensity score adjustment was found despite efforts to include patients based on SWOG 8710 study criteria [223]. These results have to be interpreted with caution, especially since no information was available for the type of NAC applied. Such analyses emphasise the importance of pragmatically designed studies that reflect real-life practice. 7.1.3 The role of imaging and predictive biomarkers Data from small imaging studies aiming to identify responders in patients treated with NAC suggest that response after two cycles of treatment is predictive of outcome. Although mpMRI has the advantage of better resolution of the bladder wall tissue planes as compared to CT, it is not ready yet for standard patient care. However, bladder mpMRI may be useful to inform on tumour stage after TURB and response to NAC [254]. So far PET/CT, MRI or DCE-MRI cannot accurately assess treatment response [255-258]. To identify progression during NAC imaging is being used in many centres notwithstanding the lack of supporting evidence. For responders to NAC, especially in those with a complete response (pT0 N0), treatment has a major positive impact on OS [259, 260]. Therefore, reliable predictive markers to identify patients most likely to benefit from chemotherapy are needed. Molecular tumour profiling might guide the use of NAC in the future but, as yet, this is not applicable in routine practice [261-263] (see Chapter 6 - Markers). 7.1.4 Role of neoadjuvant immunotherapy Inhibition of programmed death receptor-1 (PD-1)/PD-L1 checkpoint has demonstrated significant benefit in patients with unresectable and metastatic BC in the second-line setting and in platinum-ineligible PD-L1+ patients as first-line treatment using different agents. Checkpoint inhibitors are increasingly tested also in the neoadjuvant setting; either as monotherapy or in combination with chemotherapy or CTLA-4 checkpoint inhibition. Data from two phase II trials have been presented with encouraging results [208, 209]. The results of the phase II trial using the PD-1 inhibitor pembrolizumab reported a complete pathological remission (pT0) in 42% and pathological response (< pT2) in 54% of patients, whereas in the single-arm phase II trial with atezolizumab a pathologic complete response rate of 31% was reported. However, immunotherapy is not yet approved in the neoadjuvant setting. 7.1.5

Summary of evidence and guidelines for neoadjuvant therapy

Summary of evidence Neoadjuvant cisplatin-containing combination chemotherapy improves overall survival (OS) (5–8% at five years). Neoadjuvant treatment has a major impact on OS in patients who achieve ypT0 or at least ypT2. Currently immunotherapy with checkpoint inhibitors as monotherapy, or in different combinations, is being tested in phase II and III trials. Initial results are promising. There are still no tools available to select patients who have a higher probability of benefitting from NAC. In the future, genetic markers in a personalised medicine setting might facilitate the selection of patients for NAC and differentiate responders from non-responders. Neoadjuvant chemotherapy has its limitations regarding patient selection, current development of surgical techniques and current chemotherapy combinations.

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Recommendations Offer neoadjuvant chemotherapy (NAC) for T2–T4a, cN0 M0 bladder cancer. In this case, always use cisplatin-based combination therapy. Do not offer NAC to patients who are ineligible for cisplatin-based combination chemotherapy. Only offer neoadjuvant immunotherapy to patients within a clinical trial setting.

7.2

Strength rating Strong Strong Strong

Pre- and post-operative radiotherapy in muscle-invasive bladder cancer

7.2.1 Post-operative radiotherapy Given the high rates of local-regional failure after RC in patients with locally advanced (pT3–4) BC, estimated at~30%, as well as the high risk of distant failure and poor survival for these patients, there is an interest in adjuvant therapies that address both the risk of local and distant disease. Data on adjuvant RT after RC are limited and further prospective studies are needed, but a more recent phase II trial compared adjuvant sequential chemotherapy and radiation vs. adjuvant chemotherapy alone in 120 patients with locally advanced disease and negative margins after RC (with one or more risk factors: ≥ pT3b, grade 3, or node-positive), in a study population with 53% UC and 47% SCC. Addition of adjuvant RT to chemotherapy alone was associated with a statistically significant improvement in local relapse-free survival (at 2 years 96% vs. 69% favouring the addition of RT). Disease-free survival and OS also favoured the addition of RT, but those differences were not statistically significant and the study was not powered for those endpoints. Late-grade ≥ 3 gastrointestinal toxicity in the chemoradiation arm was low (7% of patients) [264]. A 2019 systematic review evaluating the efficacy of adjuvant radiation for BC or UTUC found no clear benefit of adjuvant radiation following radical surgery (e.g., cystectomy), although the combination of adjuvant radiation with chemotherapy may be beneficial in locally advanced disease [265]. While there are no conclusive data demonstrating improvements in OS it is reasonable to consider adjuvant radiation in patients with pT3/pT4 pN0–2 urothelial BC following RC, although this approach has been evaluated in only a limited number of studies. Radiation fields should encompass areas at risk for harbouring residual microscopic disease based on pathologic findings at surgery and may include cystectomy bed and pelvic LNs. Doses in the range of 45 to 50.4 Gy may be considered. For patients who have not had prior NAC, it may be reasonable to sandwich adjuvant radiation between cycles of adjuvant chemotherapy. The safety and efficacy of concurrent radiosensitising chemotherapy in the adjuvant setting needs further study. 7.2.2 Pre-operative radiotherapy To date, six RCTs have been published investigating pre-operative RT, although all are from several decades ago. In the largest trial, pre-operative RT at a dose of 45 Gy was used in patients with muscle-invasive tumours resulting in a significant increase in pathological complete response (9% to 34%) in favour of preoperative RT, which was also a prognostic factor for survival [266]. The OS data were difficult to interpret since chemotherapy was used in a subset of patients only and more than 50% of patients (241/475) did not receive the planned treatment and were excluded from the final analyses. Two smaller studies using a dose of 20 Gy showed only a small survival advantage in ≥ T3 tumours [267, 268]. Two other small trials confirmed downstaging after pre-operative RT [269, 270]. A meta-analysis of five RCTs showed a difference in 5-year survival (OR: 0.71, 95% CI: 0.48–1.06) in favour of pre-operative RT [271]. However, the meta-analysis was potentially biased by data from the largest trial in which patients were not given the planned treatment. When the largest trial was excluded from the analysis, the OR became 0.94 (95% CI: 0.57–1.55), which was not significant. A more recent RCT, comparing pre-operative vs. post-operative RT and RC (n = 100), showed comparable OS, DFS and complication rates [272]. Approximately half of these patients had UC, while the other half had SCC. In general, such older data is limited in being able to provide a robust evidence base for modern guideline recommendations.

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7.2.3

Summary of evidence and guidelines for pre- and post-operative radiotherapy

Summary of evidence No contemporary data exists to support that pre-operative RT for operable MIBC increases survival. Pre-operative RT for operable MIBC, using a dose of 45–50 Gy in fractions of 1.8–2 Gy, results in down-staging after 4 to 6 weeks. Limited high-quality evidence supports the use of pre-operative RT to decrease local recurrence of MIBC after radical cystectomy. Addition of adjuvant RT to chemotherapy is associated with an improvement in local relapse-free survival following cystectomy for locally-advanced bladder cancer (pT3b–4, or node-positive). Recommendations Do not offer pre-operative radiotherapy (RT) for operable muscle-invasive bladder cancer since it will only result in down-staging, but will not improve survival. Do not offer pre-operative RT when subsequent radical cystectomy (RC) with urinary diversion is planned. Consider offering adjuvant radiation in addition to chemotherapy following RC, based on pathologic risk (pT3b–4 or positive nodes or positive margins). 7.2.4

LE 2a 2 3 2a

Strength rating Strong Strong Weak

EAU-ESMO consensus statements on the management of advanced- and variant bladder cancer [8, 9]*

Consensus statement Candidates for curative treatment, such as cystectomy or bladder preservation, should be clinically assessed by at least an oncologist, a urologist and a neutral HCP such as a specialist nurse. When assessing patient eligibility for bladder preservation, the likelihood of successful debulking surgery should be taken into consideration (optimal debulking). *Only statements which met the a priori consensus threshold across all three stakeholder groups are listed (defined as ≥ 70% agreement and ≤ 15% disagreement, or vice versa). HCP = healthcare professional.

7.3

Radical surgery and urinary diversion

7.3.1 Removal of the tumour-bearing bladder 7.3.1.1 Introduction Radical cystectomy is the standard treatment for localised MIBC in most Western countries [212, 273]. Increased recognition of the central patient role as a healthcare consumer and a greater focus on patients’ QoL contributed to an increasing trend of utilising bladder-preserving treatment modalities, such as radioand/or chemotherapy (see Section 7.5). Performance status and life expectancy influence the choice of primary management as well as the type of urinary diversion with RC being reserved for patients with a longer life expectancy without concomitant disease and a better PS. The value of assessing overall health before proceeding with surgery was emphasised in a multivariate analysis [138]. The analysis found an association between comorbidity and adverse pathological- and survival outcomes following RC [138]. Performance status and comorbidity have a different impact on treatment outcomes and must be evaluated independently [171]. 7.3.1.2 Radical cystectomy: timing A population-based study utilising the U.S. SEER database analysed patients who underwent a RC between 1992 and 2001 and the authors concluded that a delay of > 12 weeks has a negative impact on outcome and should be avoided [274]. Moreover, the SEER analysis did not show any significant utilisation and timing differences between men and women. A 2020 meta-analysis including 19 studies confirmed these findings, showing that a longer delay of RC after diagnosis (> 3 months) was found to have a detrimental effect on OS (HR: 134, 95% CI: 1.18–1.53). The authors highlight the lack of standardisation how delays were defined in the included studies which prohibited defining a clear cut-off time, although most studies used a cut-off of < 3 months [275]. Overall conclusion was that BC patients scheduled for RC should be treated without delays to maximise survival.

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7.3.2 Radical cystectomy: indications Traditionally, RC was recommended in patients with T2–T4a, N0–Nx, M0 disease [273]. Other indications include recurrent high-risk non-muscle-invasive tumours, BCG-refractory, BCG-relapsing and BCGunresponsive NMIBC (see EAU Guidelines on Non-muscle-invasive Bladder Cancer [2]), as well as extensive papillary disease that cannot be controlled with TURB and intravesical therapy alone. Salvage cystectomy is indicated in non-responders to conservative therapy, recurrence after bladder-sparing treatment, and non-UC. It is also used as a purely palliative intervention, including for fistula formation, pain and recurrent visible haematuria (see Section 7.4.1 - Palliative cystectomy). 7.3.3 Radical cystectomy: technique and extent Different approaches have been described to improve voiding and sexual function in patients undergoing RC for BC. No consensus exists regarding which approach preserves function best. Concern remains regarding the impact of “sparing-techniques” on oncological outcomes. To determine the effect of sexual function-preserving cystectomy (SPC) on functional and oncological outcomes the Panel undertook two systematic reviews addressing sparing techniques in men and women [276, 277]. In men, standard RC includes removal of the bladder, prostate, seminal vesicles, distal ureters, and regional LNs. In women, standard RC includes removal of the bladder, the entire urethra and adjacent vagina, uterus, distal ureters, and regional LNs [278]. 7.3.3.1 Radical cystectomy in men Four main types of sexual-preserving techniques have been described: 1. Prostate sparing cystectomy: part of or the whole prostate is preserved including seminal vesicles, vas deferens and neurovascular bundles. 2. Capsule sparing cystectomy: the capsule or peripheral part of the prostate is preserved with adenoma (including prostatic urethra) removed by TURP or en bloc with the bladder. Seminal vesicles, vas deferens and neurovascular bundles are also preserved. 3. Seminal sparing cystectomy: seminal vesicles, vas deferens and neurovascular bundles are preserved. 4. Nerve-sparing cystectomy: the neurovascular bundles are the only tissue left in place. Twelve studies recruiting a total of 1,098 patients were identified, including nine comparative studies [279-289] and three single-arm case series [290-292]. In the majority of cases, an open surgical approach was used and the urinary diversion of choice was an orthotopic neobladder. Median follow-up was longer than three years in nine studies, with three studies presenting results with a median follow-up longer than five years. The majority of the studies included patients who were potent pre-operatively with organ-confined disease without tumour in the bladder neck and/or prostatic urethra. Prostate cancer was ruled out in all of the SPC techniques, except in nerve-sparing cystectomy. Oncological outcomes did not differ between groups in any of the comparative studies that measured local recurrence, metastatic recurrence, DSS and OS, at a median follow-up of three to five years. Local recurrence after SPC was commonly defined as any UC recurrence below the iliac bifurcation within the pelvic soft tissue and ranged from 1.2–61.1% vs. 16–55% in the control group. Metastatic recurrence ranged from 0–33.3%. For techniques preserving prostatic tissue (prostate- or capsule-sparing), rates of incidental prostate cancer in the intervention group ranged from 0–15%. In no case was incidental prostate cancer with ISUP grade ≥ 4 reported. Post-operative potency was significantly better in patients who underwent any type of sexualpreserving technique compared to conventional RC (p < 0.05), ranging from 80–90%, 50–100% and 29–78% for prostate-, capsule- or nerve-sparing techniques, respectively. Data did not show superiority of any sexualpreserving technique. Urinary continence, defined as the use of “no pads” in the majority of studies, ranged from 88–100% (day-time continence) and from 31–96% (night-time continence) in the prostate-sparing cystectomy patients. No major impact was shown with regard to continence rates for any of the three approaches. The evidence base suggests that these procedures may yield better sexual outcomes than standard RC without compromising oncological outcomes. However, the overall quality of the evidence was moderate, and hence if a sexual-preserving technique is offered, patients must be carefully selected, counselled and closely monitored.

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7.3.3.1.1 Summary of evidence and recommendations for sexual-preserving techniques in men Summary of evidence LE The majority of patients motivated to preserve their sexual function will benefit from sexual-preserving 2a techniques. None of the sexual-preserving techniques (prostate/capsule/seminal/nerve-sparing) have shown to be 3 superior, and no particular technique can be recommended.

Recommendations Do not offer sexual-preserving radical cystectomy to men as standard therapy for muscleinvasive bladder cancer. Offer sexual-preserving techniques to men motivated to preserve their sexual function since the majority will benefit. Select patients based on: • organ-confined disease; • absence of any kind of tumour at the level of the prostate, prostatic urethra or bladder neck.

Strength rating Strong Strong Strong

7.3.3.2 Radical cystectomy in women Pelvic floor disorders, sexual and voiding dysfunction in female patients are prevalent after RC [293]. As part of the pre-operative evaluation a gynaecological history should be obtained and patients should be counselled on the potential negative impact of RC on sexual function and/or vaginal prolapse. Most importantly, a history of cervical cancer screening, abnormal vaginal bleeding and a family history of breast and/or ovarian cancer should be recorded, as well as ruling out possible pelvic organ prolapse. Equally important is screening for sexual and urinary function and prolapse post-operatively. Better imaging modalities, increased knowledge of the function of the pelvic structures and improved surgical techniques have enabled less destructive methods for treating high-risk BC. Pelvic organ-preserving techniques involve preserving the neurovascular bundle, vagina, uterus, ovaries or variations of any of the stated techniques. From an oncological point of view, concomitant malignancy in gynaecological organs is rare and local recurrences reported after RC are infrequent [294, 295]. In premenopausal women, by preserving ovaries, hormonal homeostasis will be preserved, decreasing risk of cognitive impairment, cardiovascular diseases and loss of bone density. In case of an increased risk of hereditary breast or ovarian cancer (i.e., BRCA1/2 mutation carriers or patients with Lynch syndrome), salpingooophorectomy should be advised after childbearing and to all women over 40 years of age [296]. On the other hand, preservation of the uterus and vagina will provide the necessary support for the neobladder, thereby reducing the risk of urinary retention. It also helps to avoid post-operative prolapse as removal of the uterus predisposes to an anterior or posterior vaginal prolapse. In case of an already existing prolapse of the uterus, either isolated or combined with a vaginal prolapse, removing the uterus will be beneficial. It is noteworthy that by resecting the vaginal wall, the vagina shortens which could potentially impair sexual satisfaction and function. Based on retrospective low quality data only, a systematic review evaluating the advantages and disadvantages of sexual-function preserving RC and orthotopic neobladder in female patients concluded that in well-selected patients, sparing female reproductive organs during RC appears to be oncologically safe and provides improved functional outcomes [277]. Pelvic organ-preserving RC could be considered also in elderly and fragile patients having abdominal diversions. By reducing excision range, it might be beneficial from the point of reduced operating time, estimated blood loss and quicker bowel recovery [297]. 7.3.3.2.1 Summary of evidence and recommendations for sexual-preserving techniques in women Summary of evidence Data regarding pelvic organ-preserving RC for female patients remain immature.

LE 3

Recommendations Do not offer pelvic organ-preserving radical cystectomy to women as standard therapy for muscle-invasive bladder cancer.

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Offer sexual organ-preserving techniques to women motivated to preserve their sexual function since the majority will benefit. Select patients based on: • absence of tumour in the area to be preserved to avoid positive soft tissue margins; • absence of pT4 urothelial carcinoma.

Weak Strong

7.3.4 Lymphadenectomy: role and extent Controversies in evaluating the clinical significance of lymphadenectomy (LND) are related to two main aspects of nodal dissection: therapeutic procedure and/or staging instrument. Two important autopsy studies have been performed for RC so far. The first study showed that in 215 patients with MIBC and nodal dissemination, the frequency of metastasis was 92% in regional (perivesical or pelvic), 72% in retroperitoneal, and 35% in abdominal LNs. There was also a significant correlation between nodal metastases and concomitant distant metastases (p < 0.0001). Approximately 47% of the patients had both nodal metastases and distant dissemination and only 12% of the patients had nodal dissemination as the sole metastatic manifestation [298]. The second autopsy study focused on the nodal yield when super-extended pelvic LND was performed. Substantial inter-individual differences were found with counts ranging from 10 to 53 nodes [299]. These findings demonstrate the limited utility of node count as a surrogate for extent of dissection. Regional LNs have been shown to consist of all pelvic LNs below the bifurcation of the aorta [300304]. Mapping studies also found that skipping lesions at locations above the bifurcation of the aorta without more distally located LN metastases is rare [304, 305]. The optimal extent of LND has not been established to date. Standard LND in BC patients involves removal of nodal tissue cranially up to the common iliac bifurcation, with the ureter being the medial border, and including the internal iliac, presacral, obturator fossa and external iliac nodes [306]. Extended LND includes all LNs in the region of the aortic bifurcation, and presacral and common iliac vessels medial to the crossing ureters. The lateral borders are the genitofemoral nerves, caudally the circumflex iliac vein, the lacunar ligament and the LN of Cloquet, as well as the area described for standard LND [306-310]. A super-extended LND extends cranially to the level of the inferior mesenteric artery [311, 312]. In order to assess how and if cancer outcome is influenced by the extent of LND in patients with clinical N0M0 MIBC, a systematic review of the literature was undertaken [313]. Out of 1,692 abstracts retrieved and assessed, nineteen studies fulfilled the review criteria [306-310, 312, 314-326]. All five studies comparing LND vs. no LND reported a better oncological outcome for the LND group. Seven out of twelve studies comparing (super)extended with limited or standard LND reported a beneficial outcome for (super)extended LND in at least a subset of patients which is in concordance with the findings of several other meta-analyses [327, 328]. No difference in outcome was reported between extended and super-extended LND in the two high-volumecentre studies identified [312, 324]. The LEA trial, a prospective phase III RCT, including 401 patients with a median follow-up of 43 months recently reported [329]. Extended LND failed to show a significant advantage (the trial was designed to show an absolute improvement of 15% in 5-year RFS by extended LND) over limited LND in RFS, CSS, and OS. Results from another large RCT on the therapeutic impact of the extent of LND are expected shortly. It has been suggested that PFS as well as OS might be correlated with the number of LNs removed during surgery. Although there are no data from RCTs on the minimum number of LNs that should be removed, survival rates increase with the number of dissected LNs [330]. In retrospective studies removal of at least ten LNs has been postulated as sufficient for evaluation of LN status, as well as being beneficial for OS [331]. Submitting separate nodal packets instead of en bloc has shown significant increased total LN yield, but did not result in an increased number of positive LNs, making LN density an inaccurate prognosticator [332]. In conclusion, extended LND might have a therapeutic benefit compared to less extensive LND, but due to study bias no firm conclusions can be drawn [145, 313, 333]. 7.3.5 Laparoscopic/robotic-assisted laparoscopic cystectomy A number of recent systematic reviews comparing open RC (ORC) and robot-assisted RC (RARC) reach similar conclusions; RARC has an approximately one-day shorter length of hospital stay (LOS) and less blood loss, but a longer operative time. Complication rates seem similar for both approaches but all published reviews suffer from low quality data. In minimally-invasive cystectomy, with increasing age, LOS is markedly shorter; up to 2.56 days in patients over 80 years old [334].

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Although the low level of evidence of the studies included in these reviews remains a major limitation, a recent Cochrane review incorporating data from all five published RCTs corroborates most findings [335]. Time to recurrence, positive surgical margin rates, grade 3–5 complications and QoL were comparable for RARC and ORC, whilst transfusion rate was likely lower after RARC. For other endpoints outcomes were uncertain due to study limitations. The Pasadena Consensus Panel (a group of experts on RC, LND and urinary reconstruction) reached similar conclusions [336]. Additionally, they reported that RARC was associated with increased costs, although compared to laparoscopic RC (LRC) there are ergonomic advantages for the surgeon. For both techniques, surgeons’ experience and institutional volume strongly predicted outcome. According to the literature, proficiency is reached after 20–250 cases. However, after statistical modelling, the Pasadena Consensus Panel suggested 30 cases but they also concluded that challenging patients (high BMI, post chemotherapy or RT, pelvic surgery, T4 or bulky tumours or positive nodes) should be performed by experienced robotic surgeons only. Safety of RC after RT was confirmed by a small retrospective study (n = 46) [337]. In experienced hands the percentage of 90-day (major) complications after robotic cystectomy was independent of previous RT. A recent population-based study addressed benign uretero-enteric strictures, which appeared 5% higher after robotic - as compared to open surgery (15% vs. 9.5% at 12 months, p = 0.01) [338]. Positive surgical margins, as a surrogate for oncological outcome, are comparable between RARC and ORC, although with low certainty [335]. Recurrence-free survival, CSS and OS have been documented as similar in all RCTs including the largest RAZOR (Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer) trial (n = 302) [339]. Age over 70, poor PS and major complications were significant predictors of 36-month PFS whilst stage and positive margins were significant predictors of recurrence, PFS and OS. The surgical approach was not a significant predictor of any outcome. A larger (n = 595) single-centre study with a median follow-up of over five years also found comparable recurrence and survival data, including atypical recurrences (defined as one or a combination of the following: portsite metastasis or peritoneal carcinomatosis) [340]. However, recently, port-site metastases and atypical recurrences were reviewed by Mantica et al. [341]. Based on 31 studies and 6,720 evaluable patients, 105 patients (1.63%) were identified with an atypical recurrence, of which 63 (60%) were peritoneal carcinomatosis and 11 (10.5%) port-site metastases. The authors acknowledge, however, that these results may be linked to publication bias and retrospective study design of the included studies. Wei et al. detected residual cancer cells in pelvic washing specimens during or after, but not before, RARC in approximately half of the patients (9/17), which was associated with aggressive variant histology and cancer recurrence. These findings need confirmation in larger studies [342]. The largest RCT to date, the RAZOR trial, supports all of the above findings showing RARC to be non-inferior to ORC in terms of 2-year PFS (72.3% vs. 71.6%), adverse events (67% vs. 69%) and QoL [343]. Most reviewed series, including the RAZOR trial, offer extracorporeal reconstruction. Hussein et al. retrospectively compared extracorporeal reconstruction (n = 1,031) to intracorporeal reconstruction (n = 1,094); the latter was associated with a shorter operative time and fewer blood transfusions but more high-grade complications, which, again, decreased over time [344]. A recent retrospective report from a high-volume centre found less (major) complications after intracorporeal reconstruction (n = 301) as compared to extracorporeal reconstruction (n = 375) and open RC (n = 272) [345]. It is important to note that, although an intracorporeal neobladder is a very complex robotic procedure [346], the choice for neobladder or cutaneous diversion should not depend on the surgical approach. 7.3.5.1 Laparoscopic radical cystectomy versus robot-assisted radical cystectomy For LRC a review including sixteen studies came to similar conclusions as described for RARC [346]. As compared to ORC, LRC had a significantly longer operative time, fewer overall complications, less blood transfusions and analgesic use, less blood loss and a shorter LOS. However, the review was limited by the inherent limitations of the included studies. Although this review also showed better oncological outcomes, these appeared comparable to ORC series in a large LRC multicentre study [347]. The CORAL study was a small single-centre RCT comparing open (n = 20) vs. robotic (n = 20) vs. laparoscopic (n = 19) RC [348, 349]. The 30-day complication rate was significantly higher in the open arm (70%) compared to the laparoscopic arm (26%). There was no difference between the 90-day Clavien complication rates in the three study arms. Limitations of this study include the small sample size, three different although experienced surgeons, and cross over between arms.

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7.3.5.2

Summary of evidence and guidelines for laparoscopic/robotic-assisted laparoscopic cystectomy

Summary of evidence Robot-assisted radical cystectomy has longer operative time (1–1.5 hours) and major costs, but shorter length of hospital stay (1–1.5 days) and less blood loss compared to ORC. Robotic cystectomy and open cystectomy may result in similar rates of (major) complications. Most endpoints, if reported, including intermediate-term oncological endpoint and QoL, are not different between RARC and ORC. Surgeons experience and institutional volume are considered the key factor for outcome of both RARC and ORC, not the technique. Recommendations Inform the patient of the advantages and disadvantages of open radical cystectomy (ORC) and robot-assisted radical cystectomy (RARC) to allow selection of the proper procedure. Select experienced centres, not specific techniques, both for RARC and ORC.

LE 1 2 2 2

Strength rating Strong Strong

7.3.6 Urinary diversion after radical cystectomy From an anatomical standpoint, three alternatives are currently used after cystectomy: • abdominal diversion, such as an uretero-cutaneostomy, ileal or colonic conduit, and various forms of a continent pouch (infrequently used); • urethral diversion, which includes various forms of gastrointestinal pouches attached to the urethra as a continent, orthotopic urinary diversion (neobladder, orthotopic bladder substitution); • rectosigmoid diversions, such as uretero-(ileo-)rectostomy (infrequently used). Different types of segments of the intestinal tract have been used to reconstruct the urinary tract, including the stomach, ileum, colon and appendix [350]. Several studies have compared certain aspects of health-related quality of life (HRQoL) such as sexual function, urinary continence and body image in patient cohorts with different types of urinary diversion [351]. However, further research evaluating the impact of pre-operative tumour stage, functional- and socioeconomic status, and time interval to primary surgery are needed. 7.3.6.1 Patient selection and preparations for surgery In consultation with the patient, both an orthotopic neobladder and ileal conduit should be considered in case reconstructive surgery exposes the patient to excessive risk (as determined by comorbidity and age). Ensuring that patients make a well-informed decision about the type of urinary diversion is associated with less decision regret post-operatively, independent of the method selected [352]. Diagnosis of an invasive urethral tumour prior to cystectomy leads to urethrectomy which could be a contraindication for a neobladder reconstruction. If indicated; in males, in case of CIS and extension of tumour in the prostatic urethra, urethral frozen section has to be performed on the cystoprostatectomy specimen just under the verumontanum and on the inferior limits of the bladder neck; in females a urethral frozen section has to be taken just below the bladder neck. Non-muscle-invasive BC in prostatic urethra or bladder neck biopsies does not necessarily preclude orthotopic neobladder substitution, provided that patients undergo regular follow-up cystoscopy and urinary cytology [353]. In the presence of positive LNs, orthotopic neobladder can nevertheless be considered in case of N1 involvement (metastasis in a single node in the true pelvis) but not in N2 or N3 tumours [354]. Oncological results after orthotopic neobladder substitution or conduit diversion are similar in terms of local or distant metastasis recurrence, but secondary urethral tumours seem less common in patients with a neobladder compared to those with conduits or continent cutaneous diversions [355]. For cystectomy, general preparations are necessary as for any other major pelvic and abdominal surgery. If the urinary diversion is constructed from gastrointestinal segments, the length or size of the respective segments and their pathophysiology when storing urine must be considered [356]. Despite the necessary interruption and re-anastomosis of the bowel, formal bowel preparation may not be necessary [357]. Bowel recovery time can be reduced by the use of early mobilisation and early oralisation, gastrointestinal stimulation with metoclopramide and chewing gum [358]. Patients treated according to the “fast tract”/ERAS (Early Recovery After Surgery) protocol have shown to score better on the emotional and physical functioning scores and suffer less from wound healing disorders, fever and thrombosis [359].

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A cornerstone of the ERAS protocol is post-operative pain management, which involves significantly reducing the use of opioids; offering opioids mainly as breakthrough pain medication. Instead of patientcontrolled analgesia and epidural opioids, most patients receive high-dose acetaminophen and/or ketorolac, starting intra-operatively. Patients on ERAS experience more pain as compared to patients on a traditional protocol (Visual Analogue Scale 3.1 vs. 1.1, p < 0.001), but post-operative ileus decreased from 22% to 7.3% (p = 0.003) [360]. A multicentre randomised placebo-controlled trial showed that patients receiving alvimopan, a peripherally acting μ-opioid receptor antagonist, had quicker bowel recovery compared to patients receiving placebo [361]. However, this drug is, as yet, not approved in Europe. Venous thromboembolism (VTE) prophylaxis may be implemented as part of an ERAS protocol. A single-centre non-randomised study showed a significant lower 30-day VTE incidence rate in patients treated for 28 days with enoxaparin compared to patients without prophylaxis [362]. Data from the Ontario Cancer Registry including 4,205 cystectomy patients of whom 1,084 received NAC showed that VTE rates are higher in patients treated with NAC as compared to patients treated with cystectomy only (12% vs. 8%, p = 0.002) [363, 364]. Patients undergoing continent urinary diversion must be motivated to learn about their diversion and to be manually skilful in manipulating their diversion. Contraindications to more complex forms of urinary diversion include: • debilitating neurological and psychiatric illnesses; • limited life expectancy; • impaired liver or renal function; • urothelial carcinoma positive surgical margins. Relative contraindications specific for an orthotopic neobladder are high-dose pre-operative RT, complex urethral stricture disease and severe urethral sphincter-related incontinence [365]. 7.3.6.2 Different types of urinary diversion Radical cystectomy and urinary diversion are the two steps of one operation. However, the literature uniformly reports complications of RC while ignoring the fact that most complications are diversion related [366]. Age alone is not a criterion for offering continent diversion [365, 367]. Comorbidity, cardiac- and pulmonary function and cognitive function are all important factors that should be considered, along with the patient’s social support and preference. Age > 80 years is often considered to be the threshold after which neobladder reconstruction is not recommended. However, there is no exact age for a strict contraindication. In most large series from experienced centres, the rate of orthotopic bladder substitution after cystectomy for bladder tumour is up to 80% in men and 50% in women [368-371]. Nevertheless, no RCTs comparing conduit diversion with neobladder or continent cutaneous diversion have been performed. A retrospective study including 1,383 patients showed that the risk of a decline in estimated glomerular filtration rate (eGFR) did not significantly differ after ileal conduit vs. neobladder in patients with preoperative chronic kidney disease 2 (eGFR 60–89 mL/min/1.73 m2) or 3a (eGFR 45–59 mL/min/1.73 m2) [372]. Only age and anastomotic strictures were found to be associated with a decline in eGFR. 7.3.6.2.1 Uretero-cutaneostomy Ureteral diversion to the abdominal wall is the simplest form of cutaneous diversion. Operating time, complication rate, stay at intensive care and length of hospital stay are lower in patients treated with ureterocutaneostomy as compared to ileal conduit [373]. Therefore, in frail patients and/or in those with a solitary kidney who need a supravesical diversion, uretero-cutaneostomy is the preferred procedure [374, 375]. Quality of life, which was assessed using the Bladder Cancer Index (BCI), showed equal urinary bother and function for patients treated with ileal conduit and uretero-cutaneostomy [373]. However, others have demonstrated that in carefully selected elderly patients, all other forms of wet and dry urinary diversions, including orthotopic bladder substitutions, are possible [376]. Technically, in case patients have both kidneys; either one ureter, to which the other shorter one is attached end-to-side, is connected to the skin (trans-uretero-cutaneostomy) or both ureters are directly anastomosed to the abdominal wall creating a stoma. Due to the smaller diameter of the ureters, stoma stenosis has been observed more frequently for this technique as compared to using small or large bowel to create an intestinal stoma [374]. In a retrospective multicentre study peri-operative morbidity was evaluated for urinary diversion using bowel as compared to uretero-cutaneostomy. Patients selected for a uretero-cutaneostomy were older and had a higher ASA score, while their mean Charlson score was lower (4.2 vs. 5.6, p < 0.001) [377].

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Despite the limited comparative data available, it must be taken into consideration that older data and clinical experience suggest ureter stenosis at the skin level and ascending UTI are more frequent complications in uretero-cutaneostomy compared to an ileal conduit diversion. In a retrospective study comparing various forms of intestinal diversion, ileal conduits had fewer late complications than continent abdominal pouches or orthotopic neobladders [378]. 7.3.6.2.2 Ileal conduit The ileal conduit is still an established option with well-known/predictable results. However, up to 48% of patients develop early complications including UTIs, pyelonephritis, ureteroileal leakage and stenosis [378]. The main complications in long-term follow-up studies are stomal complications in up to 24% of patients and functional and/or morphological changes of the UUT in up to 30% [378-380]. An increase in complications was seen with longer follow-up in the Berne series of 131 patients who were followed for a minimum of five years (median follow-up 98 months) [381]; the rate of complications increased from 45% at five years to 94% in those surviving > 15 years. In the latter group, 50% of patients developed UUT changes and 38% developed urolithiasis. 7.3.6.2.3 Orthotopic neobladder An orthotopic bladder substitution to the urethra is now commonly used both in men and women. Contemporary reports document the safety and long-term reliability of this procedure. In several large centres, this has become the diversion of choice for most patients undergoing cystectomy [213, 273, 365]. However, in elderly patients (> 80 years) it is rarely performed even in high-volume expert centres [382, 383]. The terminal ileum is the gastrointestinal segment most often used for bladder substitution. There is less experience with the ascending colon, including the caecum, and the sigmoid [273]. Emptying of the reservoir anastomosed to the urethra requires abdominal straining, intestinal peristalsis, and sphincter relaxation. Early and late morbidity in up to 22% of patients is reported [384, 385]. In two studies of 1,054 and 1,300 patients [365, 386], long-term complications included diurnal (8–10%) and nocturnal (20–30%) incontinence, uretero-intestinal stenosis (3–18%), metabolic disorders, and vitamin B12 deficiency. A study comparing cancer control and patterns of disease recurrence in patients with neobladder and ileal conduit showed no difference in CSS between the two groups when adjusting for pathological stage [387]. Urethral recurrence in neobladder patients seems rare (1.5–7% in both male and female patients) [365, 388]. These results indicate that neobladder in male and female patients does not compromise the oncological outcome of cystectomy. It remains debatable whether patient’s QoL for neobladder is better compared to non-continent urinary diversion [389, 390]. Continent cutaneous urinary diversion (a low-pressure detubularised ileal reservoir for self-catheterisation) and uretero-rectosigmoidostomy are rarely used techniques nowadays, due to their high complication rates, including stomal stenosis, incontinence in the continent cutaneous diversion, UUT infections and stone formation in case of uretero-rectosigmoidostomy [391]. Various forms of UUT reflux protection, including a simple isoperistaltic tunnel, ileal intussusception, tapered ileal prolongation implanted subserosally, and direct (sub)mucosal or subserosal ureteral implantation, have been described [385, 392]. According to the long-term results, the UUT is protected sufficiently by either method. A detailed investigation of the bladder neck prior to RC is important for women who are scheduled for an orthotopic bladder substitute [393]. In women undergoing RC the rate of concomitant urethral malignancy has been reported to range from 12–16% [394]. Localisation of the primary tumour at the bladder neck correlated strongly with concomitant urethral malignancy. In addition, tumour involving the bladder neck and urethra tended to be associated with a higher risk of advanced stage and nodal involvement [395]. Currently, it is not possible to recommend a particular type of urinary diversion. However, most institutions prefer ileal orthotopic neobladders and ileal conduits based on clinical experience [396, 397]. In selected patients, such as patients with a single kidney, uretero-cutaneostomy is surgically the least burdensome type of diversion. Recommendations related to RC and urinary diversions are listed in Section 7.3.10. 7.3.7 Morbidity and mortality In three long-term studies and one population-based cohort study, the peri-operative mortality was reported as 1.2–3.2% at 30 days and 2.3–8.0% at 90 days [213, 366, 368, 398, 399]. In a large single-centre series early complications (within three months of surgery) were seen in 58% of patients [366]. Late morbidity was usually linked to the type of urinary diversion (see also above) [369, 400]. Early morbidity associated with RC

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for NMIBC (at high risk for disease progression) is similar and no less than that associated with muscle-invasive tumours [401]. In general, lower morbidity and (peri-operative) mortality have been observed by surgeons and in hospitals with a higher case load and therefore more experience [398, 402-406]. Table 7.6: Management of neobladder morbidity (30-64%) [407] CLAVIEN System Grade I

Grade II

Grade III

38

Morbidity

Management

Immediate complications: Any deviation from the normal post-operative course without Post-operative ileus Nasogastric intubation (usually the need for pharmacological removed at day 1) treatment or surgical, endoscopic Chewing gum and radiological interventions. Avoid fluid excess and hypovolemia (provoke Allowed therapeutic regimens splanchnic hypoperfusion) are: drugs such as antiemetics, Post-operative nausea Antiemetic agent antipyretics, analgesics, and vomiting (decrease opioids) diuretics and electrolytes and Nasogastric intubation physiotherapy. Urinary infection Antibiotics, no ureteral catheter removal This grade also includes wound Check the 3 drainages (ureters infections opened at the bedside. and neobladdder) Ureteral catheter Inject 5 cc saline in the obstruction ureteral catheter to resolve the obstruction Increase volume infusion to increase diuresis Check drainages and watchful Intra-abdominal urine waiting leakage (anastomosis leakage) Anaemia well tolerated Martial treatment (give iron supplement) Late complications: Non compressive Watchful waiting lymphocele Mucus cork Cough Indwelling catheter to remove the obstruction Incontinence Urine analysis (infection), echography (post-void residual) Physiotherapy Retention Drainage and selfcatheterisation education Transfusion1,2 Anaemia badly tolerated Requiring pharmacological or if myocardial treatment with drugs other cardiopathy history than those allowed for grade I complications. Blood transfusions Pulmonary embolism Heparinotherapy3 and total parenteral nutrition are Pyelonephritis Antibiotics and check kidney also included. drainage (nephrostomy if necessary) Confusion or neurological Neuroleptics and avoid opioids disorder Requiring surgical, endoscopic or Ureteral catheter Indwelling leader to raise the radiological intervention accidentally dislodged ureteral catheter Anastomosis stenosis Renal drainage (ureteral (7%) catheter or nephrostomy) Ureteral reflux No treatment if asymptomatic

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III-a

Intervention not under general anaesthesia

III-b

Intervention under general anaesthesia

Grade IV

Life-threatening complication (including central nervous system complications: brain haemorrhage, ischaemic stroke, subarachnoid bleeding, but excluding transient ischaemic attacks) requiring intensive care/ intensive care unit management. Single organ dysfunction (including dialysis) Multi-organ dysfunction

IV-a IV-b Grade V Suffix ‘d’

Compressive lymphocele

Transcutaneous drainage or intra-operative marsupialisation (cf grade III) Ileal anastomosis leakage Ileostomy, as soon as possible Evisceration Surgery in emergency Compressive lymphocele Surgery (marsupialisation) Rectal necrosis Colostomy Neobladder rupture Nephrostomy and indwelling catheter/surgery for repairing neobladder Severe sepsis Antibiotics and check all the urinary drainages and CT scan in emergency Non-obstructive renal Bicarbonate/aetiology treatment failure Obstructive pyelonephritis Nephrostomy and antibiotics and septicaemia

Death of a patient If the patient suffers from a complication at the time of discharge, the suffix “d” (for ‘disability’) is added to the respective grade of complication. This label indicates the need for a follow-up to fully evaluate the complication.

1

 systematic review showed that peri-operative blood transfusion (PBT) in patients who undergo RC A correlates with increased overall mortality, CSM and cancer recurrence. The authors hypothesised that this may be caused by the suggested immunosuppressive effect of PBT. The foreign antigens in transfused blood induce immune suppression, which may lead to tumour cell spread, tumour growth and reduced survival in already immunosuppressed cancer patients. As other possible causes for this finding increased post-operative infections and blood incompatibility were mentioned [408]. Buchner and co-workers showed similar results in a retrospective study. The 5-year CSS decreased in cases where intra-operative blood transfusion (CSS decreased from 67% to 48%) or post-operative blood transfusion (CSS decreased from 63% to 48%) were given [409].

2

Intra-operative tranexamin acid infusion reduces peri-operative blood transfusion rates from 57.7% to 31.1%. There was no increase seen in peri-operative VTE [410].

3

 ammond and co-workers reviewed 20,762 cases of VTE after major surgery and found cystectomy patients H to have the second highest rate of VTE among all cancers studied [411]. These patients benefit from 30 days low-molecular-weight heparin prophylaxis. Subsequently, it was demonstrated that BMI > 30 and nonurothelial BCs are independently associated with VTE after cystectomy. In these patients extended (90 days) heparin prophylaxis should be considered [412].

7.3.8 Survival According to a multi-institutional database of 888 consecutive patients undergoing RC for BC, the 5-year RFS rate was 58% and CSS was 66% [413]. External validation of post-operative nomograms for BC-specific mortality showed similar results, with bladder-CSS of 62% [414]. Recurrence-free survival and OS in a large single-centre study of 1,054 patients was 68% and 66% at five years and 60% and 43%, at ten years, respectively [212]. However, the 5-year RFS in node-positive patients who underwent cystectomy was considerably less at 34–43% [415, 416]. In a surgery-only study, the 5-year RFS was 76% in patients with pT1 tumours, 74% for pT2, 52% for pT3, and 36% for pT4 [212]. A trend analysis based on 148,315 BC patients identified in the SEER database between 1973 and 2009 showed increased stage-specific 5-year survival rates for all stages, except for metastatic disease [417]. 7.3.9 Impact of hospital and surgeon volume on treatment outcomes Recently, a systemic review was performed to assess the impact of hospital and/or surgeon volume on perioperative outcomes of RC [418]. In total, 40 studies including over 560,000 patients were included. All studies were retrospective cohort studies.

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Twenty-two studies reported on hospital volume only, six studies on surgeon volume only and twelve studies reported on both. The results of this systematic review suggests that a higher hospital volume is likely associated with lower in-hospital, 30-day and 90-day mortality rates. Also, higher volume hospitals are likely to have lower positive surgical margins, higher LND and neobladder rates and lower complication rates. For surgeon volume, less evidence is available and it seems that outcome after RC is mainly hospital-driven. In spite of the lower quality, the available evidence suggests that performing more than 10 RCs per year per hospital reduces 30- and 90-day mortality. Performing more than 20 RCs per hospital per year might even further reduce these mortality rates. 7.3.10

Summary of evidence and guidelines for radical cystectomy and urinary diversion

Summary of evidence Ensuring that patients are well informed about the various urinary diversion options prior to making a decision may help prevent or reduce decision regret, independent of the method of diversion selected. Higher hospital volume likely improves quality of care and reduction in peri-operative mortality and morbidity. Radical cystectomy includes removal of regional lymph nodes. There are data to support that extended lymph node dissection (LND) (vs. standard or limited LND) improves survival after RC. Radical cystectomy in both sexes must not include removal of the entire urethra in all cases, which may then serve as the outlet for an orthotopic bladder substitution. The terminal ileum and colon are the intestinal segments of choice for urinary diversion. The type of urinary diversion does not affect oncological outcome. The use of extended venous thromboembolism (VTE) prophylaxis significantly decreases the incidence of VTE after RC. In patients aged > 80 years with MIBC, cystectomy is an option. Surgical outcome is influenced by comorbidity, age, previous treatment for bladder cancer or other pelvic diseases, surgeon and hospital volumes of cystectomy, and type of urinary diversion. Surgical complications of cystectomy and urinary diversion should be reported using a uniform grading system. Currently, the best-adapted grading system for cystectomy is the Clavien grading system. No conclusive evidence exists as to the optimal extent of LND. Recommendations Do not delay radical cystectomy (RC) for > 3 months as it increases the risk of progression and cancer-specific mortality, unless the patient receives neo-adjuvant chemotherapy. Perform at least 10, and preferably > 20, RCs per hospital/per year. Before RC, fully inform the patient about the benefits and potential risks of all possible alternatives. The final decision should be based on a balanced discussion between the patient and the surgeon. Do not offer an orthotopic bladder substitute diversion to patients who have a tumour in the urethra or at the level of urethral dissection. Pre-operative bowel preparation is not mandatory. “Fast track” measurements may reduce the time to bowel recovery. Offer pharmacological prophylaxis, such as low-molecular-weight heparin to RC patients, starting the first day post-surgery, for a period of 4 weeks. Offer RC to patients with T2–T4a, N0M0 disease or high-risk non-muscle-invasive bladder cancer. Perform a lymph node dissection as an integral part of RC. Do not preserve the urethra if margins are positive.

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LE 3 3 3 3 3

3 3 3 2 2

2a

Strength rating Strong Strong Strong

Strong Strong Strong Strong Strong Strong

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7.3.11

EAU-ESMO consensus statements on the management of advanced- and variant bladder cancer [8, 9]*

Consensus statement Candidates for curative treatment, such as cystectomy or bladder preservation, should be clinically assessed by at least an oncologist, a urologist, a radiation oncologist (in case adjuvant radiotherapy or bladder preservation is considered) and a neutral healthcare professional such as a specialist nurse. Muscle-invasive pure squamous cell carcinoma of the bladder should be treated with primary radical cystectomy and lymphadenectomy. Muscle-invasive pure adenocarcinoma of the bladder should be treated with primary radical cystectomy and lymphadenectomy. T1 high-grade bladder urothelial cancer with micropapillary histology (established after complete TURBT and/ or re-TURBT) should be treated with immediate radical cystectomy and lymphadenectomy. *Only statements which met the a priori consensus threshold across all three stakeholder groups are listed (defined as ≥ 70% agreement and ≤ 15% disagreement, or vice versa). TURBT = transurethral resection of bladder tumour. Figure 7.1: Flow chart for the management of T2–T4a N0M0 urothelial bladder cancer Diagnosis • Cystoscopy and tumour resection • Evaluation of urethra1 • CT imaging of abdomen, chest, UUT • MRI can be used for local staging

Findings • cT2-4N0M0

1

– Males: biopsy apical prostatic urethra or frozen section during surgery if indicated (see below)

– Females : biopsy of proximal urethra or frozen section during surgery if indicated

cT2N0M0 selected patients – Mult modality bladder-sparing therapy can be considered for T2 tumours (Note: alternative, not the standard option )

Neo-adjuvant therapy • Chemotherapy Recommended in cisplatin-fit patients (5-8% survival benefit) • Radiotherapy Not recommended • Immunotherapy Experimental, only in clinical trial setting

Radical cystectomy

• Know general aspects of surgery - Preparation - Surgical technique - Integrated node dissection - Urinary diversion - Timing of surgery • A higher case load improves outcome

Adjuvant chemotherapy • Consider in high-risk patients only if no neo-adjuvant therapy was given

CT = computed tomography; MRI = magnetic resonance imaging; UUT = upper urinary tract.

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7.4

Unresectable tumours

7.4.1 Palliative cystectomy for muscle-invasive bladder carcinoma Locally advanced tumours (T4b, invading the pelvic or abdominal wall) may be accompanied by several debilitating symptoms, including bleeding, pain, dysuria and urinary obstruction. These patients are candidates for palliative treatments, such as palliative RT. Palliative cystectomy with urinary diversion carries the greatest morbidity and should be considered for symptom relief only if there are no other options [419-421]. Locally advanced MIBC can be associated with ureteral obstruction due to a combination of mechanical blockage by the tumour and invasion of ureteral orifices by tumour cells. In a series of 61 patients with obstructive uraemia RC was not an option in 23 patients and obstruction was relieved using permanent nephrostomy tubes [422]. Another ten patients underwent palliative cystectomy, but local pelvic recurrence occurred in all ten patients within the first year of follow-up. Another small study (n = 20) showed that primary cystectomy for T4 BC was technically feasible and associated with a very tolerable therapy-related morbidity and mortality [423]. 7.4.1.1

Guidelines for unresectable tumours

Recommendations Offer radical cystectomy as a palliative treatment to patients with inoperable locally advanced tumours (T4b). Offer palliative cystectomy to patients with symptoms. 7.4.1.2

Strength rating Weak Weak

EAU-ESMO consensus statements on the management of advanced- and variant bladder cancer [8, 9]*

Consensus statement In patients with clinical T4 or clinical N+ disease (regional), radical chemoradiation can be offered accepting that this may be palliative rather than curative in outcome. Chemoradiation should be given to improve local control in cases of inoperable locally advanced tumours. *Only statements which met the a priori consensus threshold across all three stakeholder groups are listed (defined as ≥ 70% agreement and ≤ 15% disagreement, or vice versa). 7.4.2 Supportive care 7.4.2.1 Obstruction of the upper urinary tract Unilateral (best kidney) or bilateral nephrostomy tubes provide the easiest solution for UUT obstruction, but patients find the tubes inconvenient and prefer ureteral stenting. However, stenting can be difficult to achieve. Stents must be regularly replaced and there is the risk of stent obstruction or displacement. Another possible solution is a urinary diversion with, or without, a palliative cystectomy. 7.4.2.2 Bleeding and pain In the case of bleeding, the patient must be screened first for coagulation disorders or the patient’s use of anticoagulant drugs must be reviewed. Transurethral (laser) coagulation may be difficult in a bladder full of tumour or with a bleeding tumour. Intravesical rinsing of the bladder with 1% silver nitrate or 1–2% alum can be effective [424]. This can usually be done without any anaesthesia. The instillation of formalin (2.5–4% for 30 minutes) is a more aggressive and painful procedure, requiring anaesthesia. Formalin instillation has a higher risk of side-effects, e.g., bladder fibrosis, but is more likely to control the bleeding [424]. Vesicoureteral reflux should be excluded to prevent renal complications. Radiation therapy is another common strategy to control bleeding and is also used to control pain. An older study reported control of haematuria in 59% of patients and pain control in 73% [425]. Irritative bladder and bowel complaints due to irradiation are possible, but are usually mild. Non-conservative options are embolisation of specific arteries in the small pelvis, with success rates as high as 90% [424]. Radical surgery is a last resort and includes cystectomy and diversion (see above, Section 7.4.1).

7.5

Bladder-sparing treatments for localised disease

7.5.1 Transurethral resection of bladder tumour Transurethral resection of bladder tumour alone in MIBC patients is only possible as a therapeutic option if tumour growth is limited to the superficial muscle layer and if re-staging biopsies are negative for residual (invasive) tumour [426]. In general, approximately 50% of patients will still have to undergo RC for recurrent

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MIBC with a disease-specific mortality rate of up to 47% within this group [427]. A disease-free status at re-staging TURB appears to be crucial in making the decision not to perform RC [428, 429]. A prospective study by Solsona et al. including 133 patients with radical TURB and re-staging negative biopsies, reported a 15-year follow-up [429]. Thirty per cent of patients had recurrent NMIBC and went on to intravesical therapy, and 30% (n = 40) progressed, of which 27 died of BC. After five, ten, and fifteen years, the results showed CSS rates of 81.9%, 79.5%, and 76.7%, respectively and PFS rates with an intact bladder of 75.5%, 64.9%, and 57.8%, respectively. In conclusion, TURB alone should only be considered as a therapeutic option for muscle-invasive disease after radical TURB, when the patient is unfit for cystectomy, or refuses open surgery, or as part of a multimodality bladder-preserving approach. 7.5.1.1

Guideline for transurethral resection of bladder tumour

Recommendation Do not offer transurethral resection of bladder tumour alone as a curative treatment option as most patients will not benefit.

7.5.1.2

Strength rating Strong

EAU-ESMO consensus statements on the management of advanced- and variant bladder cancer [8, 9]*

Consensus statement Candidates for curative treatment, such as cystectomy or bladder preservation, should be clinically assessed by at least an oncologist, a urologist, a radiation oncologist (in case adjuvant radiotherapy or bladder preservation is considered) and a neutral HCP such as a specialist nurse. An important determinant for patient eligibility in case of bladder-preserving treatment is absence of carcinoma in situ. An important determinant for patient eligibility in case of bladder-preserving treatment is absence or presence of hydronephrosis. When assessing patient eligibility for bladder preservation, the likelihood of successful debulking surgery should be taken into consideration (optimal debulking). *Only statements which met the a priori consensus threshold across all three stakeholder groups are listed (defined as ≥ 70% agreement and ≤ 15% disagreement, or vice versa). HCP = healthcare professional. 7.5.2 External beam radiotherapy Current RT techniques with soft-tissue matching and image guidance result in superior bladder coverage and a reduced integral dose to the surrounding tissues. The target total dose (to bladder and/or bladder tumour) for curative EBRT in BC is 64–66 Gy [430, 431]. A reasonable alternative is moderately hypofractionated EBRT to 55 Gy in 20 fractions which has been suggested to be non-inferior to 64 Gy in 32 fractions in terms of invasive locoregional control, OS, and late toxicity. In a phase II study, 55 patients (median age 86) with BC, unfit for cystectomy or even daily RT, were treated with 6-weekly doses of 6 Gy [432]. Forty-eight patients completed EBRT with acceptable toxicity and 17% showed local progression after two years demonstrating good local control with this more ultra-hypofractionated schedule. Elective treatment to the LNs is optional and should take into account patient comorbidities and the risks of toxicity to adjacent critical structures. For node-positive disease, consider boosting grossly involved nodes to the highest achievable dose that does not violate normal tissue constraints based on the clinical scenario. The use of modern standard EBRT techniques results in major related late morbidity of the urinary bladder or bowel in less than 5% of patients [433]. Acute diarrhoea is reduced even more with intensitymodulated RT [434]. Important prognostic factors for outcome include response to EBRT, tumour size, hydronephrosis, presence of CIS, and completeness of the initial TURB. Additional prognostic factors reported are age and stage [435]. With the use of modern EBRT techniques, efficacy and safely results seem to have improved over time. A 2002 Cochrane analysis demonstrated that RC has an OS benefit compared to RT [436], although this was not the case in a 2014 retrospective review using a propensity score analysis [437]. In a 2017 retrospective cohort study of U.S. National Cancer Data Base data, patients over 80 were identified with cT2–4, N0–3, M0 BC, who were treated with curative EBRT (60–70 Gy, n = 739) or concurrent chemoradiotherapy (n = 630) between 2004 and 2013 [438]. The 2-year OS was 42% for EBRT vs. 56% for chemoradiotherapy (p < 0.001). For EBRT a higher RT dose and a low stage were associated with improved OS. LIMITED UPDATE MARCH 2021

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In conclusion, although EBRT results seem to improve over time, EBRT alone does not seem to be as effective as surgery or trimodality therapy (see Section 7.5.4). Factors that influence outcome should be considered. However, EBRT can be an alternative treatment in patients unfit for radical surgery or concurrent chemotherapy, and it can also be quite effective in helping control bleeding. 7.5.2.1

Summary of evidence and guideline for external beam radiotherapy

Summary of evidence LE External beam radiotherapy alone should only be considered as a therapeutic option when the patient 3 is unfit for cystectomy. Radiotherapy can also be used to stop bleeding from the tumour when local control cannot be 3 achieved by transurethral manipulation because of extensive local tumour growth.

Recommendation Do not offer radiotherapy alone as primary therapy for localised bladder cancer.

7.5.2.2

Strength rating Strong

EAU-ESMO consensus statements on the management of advanced- and variant bladder cancer [8, 9]*

Consensus statement Radiotherapy alone (single block) is not the preferred radiotherapeutic schedule. Radiotherapy for bladder preservation should be performed with IMRT and IGRT to reduce side effects. Dose escalation above standard radical doses to the primary site in case of bladder preservation, either by IMRT or brachytherapy, is not recommended. *Only statements which met the a priori consensus threshold across all three stakeholder groups are listed (defined as ≥ 70% agreement and ≤ 15% disagreement, or vice versa). IGRT = image-guided radiotherapy; IMRT = intensity-modulated radiotherapy. 7.5.3 Chemotherapy Chemotherapy alone rarely produces durable complete remissions. In general, a clinical complete response rate of up to 56% is reported in some series, which must be weighed against a staging error of > 60% [439, 440]. Response to chemotherapy is a prognostic factor for treatment outcome and eventual survival although it may be confounded by patient selection [441]. Several groups have reported the effect of chemotherapy on resectable tumours (neoadjuvant approach), as well as unresectable primary tumours [223, 240, 442, 443]. Neoadjuvant chemotherapy with two to three cycles of MVAC or CMV has led to a down-staging of the primary tumour in various prospective series [223, 240, 442]. A bladder-conserving strategy with TURB and systemic cisplatin-based chemotherapy has been reported several years ago and could lead to long-term survival with intact bladder in a highly selected patient population [441]. A recent large retrospective analysis of a National Cancer Database cohort reported on 1,538 patients treated with TURB and multi-agent chemotherapy [444]. The two and 5-year OS for all patients was 49% and 32.9% and for cT2 patients it was 52.6% and 36.2%, respectively. While these data show that longterm survival with intact bladder can be achieved in a subset of patients it is not recommended for routine use. 7.5.3.1

Summary of evidence and guideline for chemotherapy

Summary of evidence Complete and partial local responses have been reported with cisplatin-based chemotherapy as primary therapy for locally advanced tumours in highly selected patients.

Recommendation Do not offer chemotherapy alone as primary therapy for localised bladder cancer.

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LE 2b

Strength rating Strong

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7.5.4 Trimodality bladder-preserving treatment Trimodality therapy (TMT) combines TURB, chemotherapy and RT. The rationale to combine TURB with RT is to maximally achieve local tumour control in the bladder and adjacent nodes. The addition of radiosensitising chemotherapy or other radiosensitisers (mentioned below) is aimed at the potentiation of RT. Micrometastases are targeted by platinum-based combination chemotherapy (for details see Section 7.1). The aim of TMT is to preserve the bladder and QoL without compromising oncological outcome. There are no successfully completed RCTs comparing the outcome of TMT with RC, but TMT using chemoradiation has been shown to be superior to RT alone [445, 446]. Many of the reported series have differing characteristics as compared to the larger surgical series, which typically have median ages in the midto-late 60s compared to mid-70s for some large RT series (reviewed by James, et al. [445]). In the case of TMT, two distinct patterns of care emerge; treatment aimed at patients fit for cystectomy who elect TMT or refuse cystectomy, and treatment aimed at older, less fit, patients. For the former category, TMT presents selective bladder preservation and in this case the initial step is a radical TURB where as much tumour as possible should be resected. In this case appropriate patient selection (e.g., T2 tumours, no CIS) is critical [447, 448]. Even in case of an initial presumed complete resection, a second TUR has been suggested to reveal tumour in > 50% of patients and subsequently improves 5-year OS in case of TMT [449]. For patients who are not candidates for cystectomy, less stringent criteria can be applied, but extensive CIS and poor bladder function should both be regarded as relative contraindications. A collaborative review has described the principles of TMT [450]. For radiation, two schedules are most commonly used; historically within the RTOG a split-course format with interval cystoscopy [446] and singlephase treatment which is now more commonly used [445]. A conventional radiation schedule includes EBRT to the bladder and limited pelvic LNs with an initial dose of 40-45 Gy, with a boost to the whole bladder of 50–54 Gy and a further tumour boost to a total dose of 60–66 Gy. If not boosting the tumour, it is also reasonable for the whole bladder to be treated to 59.4–66 Gy. For node-positive disease, consider boosting grossly involved nodes to the highest achievable dose that does not violate normal tissue constraints. Therefore, elective treatment to the LNs (when node negative) is optional and should take into account patient comorbidities and the risks of toxicity to adjacent critical structures. In summary, reasonable radiation fields include pelvis (with bladder and/or bladder tumour boost), bladder only or partial bladder (tumour) only [445]. A reasonable radiation dosing alternative to conventional fractionation when treating the bladder-only fields is moderately hypofractionated EBRT to 55 Gy in 20 fractions which has been suggested to be non-inferior to 64 Gy in 32 fractions (fx) in terms of invasive loco-regional control, OS and late toxicity [430, 451]. Different chemotherapy regimens have been used, but most evidence exists for cisplatin [452] and mitomycin C plus 5-FU [445]. In addition to these agents, other regimens have also been used such as gemcitabine and hypoxic cell sensitisation with nicotinamide and carbogen, without clear preference for a specific radiosensitiser [8, 9]. In a recently published phase II RCT, twice-a-day radiation plus fluorouracil/cisplatin was compared to once-daily radiation plus gemcitabine [453]. Both arms were found to result in a > 75% freedom of distant metastases at 3 years (78% and 84%, respectively). Therefore, there are options for non-cisplatin candidates such as 5-FU/mitomycin C or low-dose gemcitabine. To detect non-responders who should be offered salvage cystectomy, bladder biopsies should be performed after TMT and life-long cystoscopic surveillance is recommended. Five-year CSS and OS rates vary between 50%–84% and 36%–74%, respectively, with salvage cystectomy rates of 10–30% [445, 447, 450, 452, 454, 455]. The Boston group reported on their experience in 66 patients with mixed variant histologies treated with TMT and found similar complete response, OS, DSS and salvage cystectomy rates as in UC [456]. The majority of recurrences post-TMT are non-invasive and can be managed conservatively [445]. In contemporary experiences, salvage cystectomy is required in about 10–15% of patients treated with TMT and can be curative [445, 447, 455]. Current data suggest that major late complication rates are slightly higher but remain acceptable for salvage- vs. primary cystectomy [457, 458]. A sub-analysis of two RTOG trials looked at complete response (T0) and near-complete response (Ta or Tis) after TMT [459]. After a median follow-up of 5.9 years 41/119 (35%) of patients experienced a bladder recurrence, and fourteen required salvage cystectomy. There was no difference between complete and nearcomplete responders. Non-muscle-invasive BC recurrences after complete response to TMT were reported in 25% of patients by the Boston group, sometimes over a decade after initial treatment [460]. A NMIBC

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recurrence was associated with a lower DSS, although in properly selected patients, intravesical BCG could avoid immediate salvage cystectomy. The differential impact of RC vs. TMT on long-term OS is lacking a randomised comparison and rigorous prospective data. A propensity score matched institutional analysis has suggested similar DSS and OS between TMT and RC [455]. Two retrospective analyses of the National Cancer Database from 2004–2013 with propensity score matching compared RC to TMT. Ritch et al. identified 6,606 RC and 1,773 TMT patients [461]. Worse survival was linked to higher age, comorbidity and tumour stage. After modelling, TMT resulted in a lower mortality at one year (HR: 0.84, 95% CI: 0.74–0.96, p = 0.01). However, in years 2 and onwards, there was a significant and persistent higher mortality after TMT (year 2: HR: 1.4, 95% CI: 1.2–1.6, p < 0.001; and year 3 onwards: HR: 1.5, 95% CI: 1.2–1.8, p < 0.001). The second analysis was based on a larger cohort, with 22,680 patients undergoing RC; 2,540 patients received definitive EBRT and 1,489 TMT [462]. Survival after modelling was significantly better for RC compared to any EBRT, definitive EBRT and TMT (HR: 1.4, 95% CI: 1.2–1.6) at any time point. In older patients which are potentially less ideal candidates for radical surgery, Williams et al. found a significantly lower OS (HR :1.49, 1.31–1.69) and CSS (1.55, 1.32–1.83) for TMT as compared to surgery as well as increased costs [463]. This was a retrospective SEER database study which included 687 propensity-matched patients in each arm, however, the median number of radiation fractions was well below what is considered adequate for definitive therapy and as such the radiation patients may have been treated inadequately or palliatively. In general, such population-based studies are limited by confounding, misclassification, and selection bias. A systematic review including 57 studies and over 30,000 patients comparing RC and TMT found improved 10-year OS and DSS for TMT, but for the entire cohort OS and DSS did not significantly differ between RC and TMT [464]. Complete response after TMT resulted in significantly better survival, as did down-staging after TURB or NAC in case of RC. Overall significant late pelvic (GI/genitourinary [GU]) toxicity rates after TMT are low and QoL is good [445, 465, 466]. A combined analysis of survivors from four RTOG trials with a median follow-up of 5.4 years showed that combined-modality therapy was associated with low rates of late grade 3 toxicity (5.7% GU and 1.9% GI). No late grade 4 toxicities or treatment-related deaths were recorded [465]. A retrospective study showed QoL to be good after TMT and in most domains better than after cystectomy, although prospective validations are needed [467]. One option to reduce side effects after TMT is the use of IMRT and image-guided radiotherapy (IGRT) [8, 9, 468]. A collaborative review came to the conclusion that data are accumulating, suggesting that bladder preservation with TMT leads to acceptable outcomes and therefore TMT may be considered a reasonable treatment option in well-selected patients as compared to RC [450]. Bladder preservation as an alternative to RC is generally reserved for patients with smaller solitary tumours, negative nodes, no extensive or multifocal CIS, no tumourrelated hydronephrosis, and good pre-treatment bladder function. Trimodality bladder-preserving treatment should also be considered in all patients with a contraindication for surgery, either a relative or absolute contraindication since the factors that determine fitness for surgery and chemoradiotherapy differ. There are no definitive contemporary data supporting the benefit of using neoadjuvant or adjuvant chemotherapy combined with chemoradiation. Patient selection is critical in achieving good outcomes [450]. Whether a node dissection should be performed before TMT as in RC remains unclear [8, 9]. A bladder-preserving trimodality strategy requires very close multidisciplinary cooperation [8, 9]. This was also highlighted by a Canadian group [469]. In Ontario between 1994 and 2008 only 10% (370/3,759) of patients with cystectomy had a pre-operative radiation oncology consultation, with high geographical variations. Independent factors associated with this consultation included advanced age (p < 0.001), greater comorbidity (p < 0.001) and earlier year of diagnosis (p < 0.001). A bladder-preserving trimodality strategy also requires a high level of patient compliance. Even if a patient has shown a clinical response to a trimodality bladderpreserving strategy, the bladder remains a potential source of recurrence, hence long-term life-long bladder monitoring is essential and patients should be counselled that this will be required. 7.5.4.1

Summary of evidence and guidelines for trimodality bladder-preserving treatment

Summary of evidence In a selected patient population, long-term survival rates of trimodality bladder-preserving treatment are comparable to those of early cystectomy.

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Recommendations Strength rating Offer surgical intervention or trimodality bladder-preserving treatments (TMT) to appropriate Strong candidates as primary curative therapeutic approaches since they are more effective than radiotherapy alone. Offer TMT as an alternative to selected, well-informed and compliant patients, especially for Strong whom radical cystectomy is not an option or not acceptable. 7.5.4.2

EAU-ESMO consensus statements on the management of advanced- and variant bladder cancer [8, 9]*

Consensus statement Candidates for curative treatment, such as cystectomy or bladder preservation, should be clinically assessed by at least an oncologist, a urologist, a radiation oncologist (in case adjuvant radiotherapy or bladder preservation is considered) and a neutral HCP such as a specialist nurse. An important determinant for patient eligibility in case of bladder-preserving treatment is absence of carcinoma in situ. An important determinant for patient eligibility in case of bladder-preserving treatment is absence or presence of hydronephrosis. When assessing patient eligibility for bladder preservation, the likelihood of successful debulking surgery should be taken into consideration (optimal debulking). Bladder urothelial carcinoma with small cell neuroendocrine variant should be treated with neoadjuvant chemotherapy followed by consolidating local therapy. In case of bladder preservation with radiotherapy, combination with a radiosensitiser is always recommended to improve clinical outcomes, such as cisplatin, 5FU/TMC, carbogen/nicotinamide or gemcitabine. Radiotherapy for bladder preservation should be performed with IMRT and IGRT to reduce side effects. Dose escalation above standard radical doses to the primary site in case of bladder preservation, either by IMRT or by brachytherapy, is not recommended. *Only statements which met the a priori consensus threshold across all three stakeholder groups are listed (defined as ≥ 70% agreement and ≤ 15% disagreement, or vice versa). HCP = healthcare professional; IGRT = image-guided radiotherapy; IMRT = intensity-modulated radiotherapy; 5FU = 5-fluorouracil; MMC = mitomycin-C.

7.6

Adjuvant therapy

7.6.1 Role of adjuvant platinum-based chemotherapy Adjuvant chemotherapy after RC for patients with pT3/4 and/or LN positive (N+) disease without clinically detectable metastases (M0) is still under debate [457, 470]. The general benefits of adjuvant chemotherapy include: • chemotherapy is administered after accurate pathological staging, therefore, treatment in patients at low risk for micrometastases is avoided; • no delay in definitive surgical treatment. The drawbacks of adjuvant chemotherapy are: • assessment of in vivo chemosensitivity of the tumour is not possible and overtreatment is an unavoidable problem; • delay or intolerability of chemotherapy, due to post-operative morbidity [471]. There is limited evidence from adequately conducted and accrued phase III RCTs in favour of the routine use of adjuvant chemotherapy [470, 472-477]. An individual patient data meta-analysis [472] of survival data from six RCTs of adjuvant chemotherapy [454, 478-481] included 491 patients (unpublished data from Otto et al., were included in the analysis). All included trials suffered from significant methodological flaws including small sample size (underpowered), incomplete accrual, use of inadequate statistical methods and design flaws (irrelevant endpoints and failing to address salvage chemotherapy in case of relapse or metastases) [470]. In these trials, three or four cycles of CMV, cisplatin, cyclophosphamide, and adriamycin (CISCA), methotrexate, vinblastine, adriamycin or epirubicin, and cisplatin (MVA(E)C) and cisplatin and methotrexate (CM) were used [482], and one trial used cisplatin monotherapy [480]. The data were not convincing to support an unequivocal recommendation for the use of adjuvant chemotherapy. In 2014, this meta-analysis was updated with an additional three studies [474-476] resulting in the inclusion of 945 patients from nine trials [473]. None of the trials had fully accrued and individual patient data were not used in the analysis [473]. For one trial only an abstract was available at the time of the meta-analysis [475] and none of the included individual trials were significantly positive for OS in favour of adjuvant chemotherapy. In two of the trials more modern chemotherapy

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regimens were used (gemcitabine/cisplatin and paclitaxel/gemcitabine/cisplatin) [474, 475]. The HR for OS was 0.77 (95% CI: 0.59–0.99, p = 0.049) and for DFS 0.66 (95% CI: 0.45–0.91, p = 0.014) with a stronger impact on DFS in case of nodal positivity. A retrospective cohort analysis including 3,974 patients after cystectomy and LND showed an OS benefit in high-risk subgroups (extravesical extension and nodal involvement) (HR: 0.75, CI: 0.62–0.90) [483]. A recent publication of the largest RCT (EORTC 30994), although not fully accrued, showed a significant improvement of PFS for immediate, compared with deferred, cisplatin-based chemotherapy (HR: 0.54, 95% CI: 0.4–0.73, p < 0.0001), but there was no significant OS benefit [484]. Furthermore, a large observational study including 5,653 patients with pathological T3–4 and/ or pathological node-positive BC, treated between 2003 and 2006 compared the effectiveness of adjuvant chemotherapy vs. observation. Twenty-three percent of patients received adjuvant chemotherapy with a 5-year OS of 37% for the adjuvant arm vs. 29.1% (HR: 0.70, 95% CI: 0.64–0.76) in the observation group [485]. Another large retrospective analysis based on National Cancer Data Base including 15,397 patients with locally advanced (pT3/4) or LN-positive disease also demonstrated an OS benefit in patients with UC histology [486]. In patients with concomitant variant or pure variant histology, however, no benefit was found. From the currently available evidence it is still unclear whether immediate adjuvant chemotherapy or chemotherapy at the time of relapse is superior, or if the two approaches are equivalent with respect to the endpoint of OS. The most recent meta-analysis from 2014 showed a therapeutic benefit of adjuvant chemotherapy, but the level of evidence of this review is still very low, with significant heterogeneity and methodological flaws in the only nine included trials [473]. Patients should be informed about potential chemotherapy options before RC, including neoadjuvant and adjuvant chemotherapy, and the limited evidence for adjuvant chemotherapy. 7.6.2 Role of adjuvant immunotherapy To evaluate the benefit of PD-1/PD-L1 checkpoint inhibitors, a number of randomised phase III trials comparing checkpoint inhibitor monotherapy with atezolizumab, nivolumab or pembrolizumab are under way. Preliminary results of two phase III trials have been presented (atezolizumab at ASCO 2020; nivolumab at ASCO GU 2021): the primary endpoint of improved DFS was not achieved with atezolizumab but was achieved with adjuvant nivolumab. Further results and longer follow-up have to be awaited. So far, adjuvant immunotherapy is not standard of care and should only be given within a clinical trial [487]. 7.6.3

Guidelines for adjuvant therapy

Recommendations Offer adjuvant cisplatin-based combination chemotherapy to patients with pT3/4 and/or pN+ disease if no neoadjuvant chemotherapy has been given. Only offer immunotherapy with a checkpoint inhibitor in a clinical trial setting.

7.7

Strength rating Strong Strong

Metastatic disease

7.7.1 Introduction Approximately 50% of patients with muscle-invasive UC relapse after RC, depending on the pathological stage of the primary tumour and the nodal status. Local recurrence accounts for 30% of relapses, whereas distant metastases are more common. Ten to fifteen percent of patients are already metastatic at diagnosis [488]. Before the development of effective chemotherapy patients with metastatic UC had a median survival rarely exceeding three to six months [489]. 7.7.1.1 Prognostic factors and treatment decisions Prognostic factors are crucial for assessing phase II study results and stratifying phase III trials [490, 491]. In a multivariate analysis, Karnofsky PS of ≤ 80% and presence of visceral metastases were independent prognostic factors of poor survival after treatment with MVAC [491]. These prognostic factors have also been validated for newer combination chemotherapy regimens [492-496]. Two additional prognostic models have been developed in the past years including the variables leukocyte count, number of sites of visceral metastases, site of primary tumour, PS, LN metastasis [496] and visceral metastasis, albumin and haemoglobin [495], respectively. For patients refractory to, or progressing shortly after, platinum-based combination chemotherapy, four prognostic groups have been established based on three adverse factors that have developed in patients treated with vinflunine and that have been validated in an independent data set; Hb < 10 g/dL presence of liver

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metastases and ECOG PS ≥ 1 [497]. It is important to acknowledge that these prognostic models have not been validated in the context of newer agents including immunotherapy. 7.7.1.2 Comorbidity in metastatic disease Comorbidity is defined as “the presence of one or more disease(s) in addition to an index disease” (see Section 5.3). Comorbidity increases with age. However, chronological age does not necessarily correlate with functional impairment. Different evaluation systems are being used to screen patients as potentially fit or unfit for chemotherapy, but age alone should not be used as the basis for treatment selection [498]. 7.7.2 First-line systemic therapy for metastatic disease In general, patients with untreated metastatic BC can be divided into three broad categories: fit for cisplatinbased chemotherapy, fit for carboplatin-based chemotherapy (but unfit for cisplatin) and unfit for any platinumbased chemotherapy. 7.7.2.1 Definitions: ‘Fit for cisplatin, fit for carboplatin, unfit for any platinum-based chemotherapy’ An international survey among BC experts [499] was the basis for a consensus statement on how to classify patients unfit for cisplatin-based chemotherapy. At least one of the following criteria has to be present: PS > 1; GFR ≤ 60 mL/min; grade ≥ 2 audiometric loss; grade ≥ 2 peripheral neuropathy or New York Heart Association (NYHA) class III heart failure [500]. More than 50% of patients with UC are not eligible for cisplatin-based chemotherapy [501-504]. Renal function assessment in UC is of utmost importance for treatment selection [501, 505]. In case of doubt, measuring GFR with radioisotopes (99mTc DTPA or 51Cr-EDTA) is recommended. Cisplatin has also been administered in patients with a lower GFR (40–60 mL/min) using different split-dose schedules. The respective studies were mostly small phase I and II trials in different settings (neoadjuvant and advanced disease) demonstrating that the use of split-dose cisplatin is feasible and appears to result in encouraging efficacy [506-509]. However, no prospective randomised trial has compared split-dose cisplatin with conventional dosing. Most patients that are deemed unfit for cisplatin are able to receive carboplatin-based chemotherapy. However, some patients are deemed unfit for any platinum-based chemotherapy (both cisplatin and carboplatin) in case of PS > 2, impaired renal function with a GFR < 30 mL/min or the combination of PS 2 and GFR < 60 mL/min since the outcome in this patient population is poor regardless of platinum-based treatment or not [510]. Patients with multiple comorbidities may also be poor candidates for platinum-based chemotherapy. 7.7.2.2 Chemotherapy in patients fit for cisplatin Cisplatin-containing combination chemotherapy has been the standard of care since the late 1980s demonstrating an OS of twelve to fourteen months in different series (for a review see [511]). Methotrexate, vinblastine, adriamycin plus cisplatin (MVAC) and GC prolonged survival to up to 14.8 and 13.8 months, respectively, compared to monotherapy and older chemotherapy combinations. Neither of the two combinations is superior to the other but equivalence has not been tested. Response rates were 46% and 49% for MVAC and GC, respectively. The long-term survival results have confirmed the efficacy of the two regimens [512]. The major difference between the above-mentioned combinations is toxicity. The lower toxicity of GC [174] compared to standard MVAC has resulted in it becoming a new standard regimen [513]. Methotrexate, vinblastine, adriamycin plus cisplatin is better tolerated when combined with granulocyte colony-stimulating factor (G-CSF) [513, 514]. High-dose intensity MVAC (HD-MVAC) combined with G-CSF is less toxic and more efficacious than standard MVAC in terms of dose density, complete response (CR), and 2-year survival rate. However, there is no significant difference in median survival between the two regimens [515, 516]. In general, all disease sites have been shown to respond to cisplatin-based combination chemotherapy. A response rate of 66% and 77% with MVAC and HD-MVAC, respectively, has been reported in retroperitoneal LNs vs. 29% and 33% at extranodal sites [515]. The disease sites also have an impact on long-term survival. In LN-only disease, 20.9% of patients were alive at five years compared to only 6.8% of patients with visceral metastases [512]. Further intensification of treatment using paclitaxel, cisplatin and gemcitabine (PCG) triple regimen did not result in a significant improvement in OS in the intention-to-treat (ITT) population of a large phase III RCT, comparing PCG triple regimen to GC [517]. However, the overall response rate (ORR) was higher with the triple regimen (56% vs. 44%, p = 0.0031), and the trend for OS improvement in the ITT population (15.8 vs. 12.7 months; HR = 0.85, p = 0.075) became significant in the eligible population. Carboplatin-containing chemotherapy has not been proven to be equivalent to cisplatin combinations, and should not be considered interchangeable or standard in patients fit for cisplatin. Several phase II RCTs of

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carboplatin vs. cisplatin combination chemotherapy have produced lower CR rates and shorter OS for the carboplatin arms [518]. Recently, a retrospective International Study of Advanced/Metastatic Cancer of the Urothelium (RISC) group highlighted the importance of applying the cisplatin-eligibility criteria in order to maintain benefit [519]. 7.7.2.3 Chemotherapy in patients fit for carboplatin (but unfit for cisplatin) Up to 50% of patients are not fit for cisplatin-containing chemotherapy but may be candidates for carboplatin [500]. The first randomised phase II/III trial in this setting was conducted by the EORTC and compared two carboplatin-containing regimens (methotrexate/carboplatin/vinblastine [M-CAVI] and carboplatin/gemcitabine [GemCarbo]) in patients unfit for cisplatin. The EORTC definitions for eligibility were GFR < 60 mL/min and/or PS 2. Both regimens were active. Severe acute toxicity was 13.6% in patients treated with GemCarbo vs. 23% with M-CAVI, while the ORR was 42% for GemCarbo and 30% for M-CAVI. Further analysis showed that in patients with PS 2 and impaired renal function, combination chemotherapy provided very limited benefit [510]. The ORR and severe acute toxicity were both 26% for the former group, and 20% and 24%, respectively, for the latter group [510]. Phase III data have confirmed these results [494]. The combination of carboplatin and gemcitabine can be considered a standard of care in this patient group. A randomised, international phase II trial (JASINT1; JAVLOR Association Study in CDDP-unfit Patients With Advanced Transitional Cell Carcinoma: Gemcitabine Versus Carboplatin) assessed the efficacy and tolerability profile of two vinflunine-based regimens (vinflunine/gemcitabine vs. vinflunine/carboplatin). Both regimens showed equal ORR and OS with less haematologic toxicity for the combination vinflunine/ gemcitabine [520]. 7.7.2.4

Integration of immunotherapy in the first-line treatment of patients fit for platinum-based chemotherapy 7.7.2.4.1 Immunotherapy combination approaches In 2020 the results of three phase III trials have been presented and published investigating the use of immunotherapy in the first-line setting for platinum-eligible patients. The first trial to report was IMvigor130 investigating the combination of the PD-L1 inhibitor atezolizumab plus platinum-gemcitabine chemotherapy vs. chemotherapy plus placebo vs. atezolizumab alone [521]. The primary endpoint of PFS benefit for the combination vs. chemotherapy alone in the ITT group was reached (8.2 months vs. 6.3 months [HR: 0.82, 95% CI: 0.70–0.96; one-sided, p = 0.007]) while OS was not significant at the interim analysis after a median follow-up of 11.8 months. The small PFS benefit in the absence of an OS benefit has raised questions of its clinical significance. Due to the sequential testing design, the comparison of chemotherapy vs. atezolizumab alone has not yet been formally performed. The KEYNOTE 361 study had a very similar design using the PD-1 inhibitor pembrolizumab plus platinum-gemcitabine vs. chemotherapy alone vs. pembrolizumab alone. The results of the primary endpoints of PFS and OS for the comparison of pembrolizumab plus chemotherapy vs. chemotherapy in the ITT population have been presented but are not yet fully published and show no benefit for the combination [522]. DANUBE compared the immunotherapy combination (IO-IO) of CTLA-4 inhibitor tremelimumab and PD-L1 inhibitor durvalumab with chemotherapy alone or durvalumab alone [523]. The co-primary endpoint of improved OS for the IO-IO combination vs. chemotherapy was not reached in the ITT group nor was the OS improved for durvalumab monotherapy vs. chemotherapy in the PD-L1-positive population. In conclusion; at this time these three trials do not support the use of combination of PD-1/L1 checkpoint inhibitors plus chemotherapy or the IO-IO combination. 7.7.2.4.2 Use of single-agent immunotherapy Based on the results of two single-arm phase II trials [524, 525] the checkpoint inhibitors pembrolizumab and atezolizumab have been approved by the FDA and the EMA for first-line treatment in cisplatin-unfit patients in case of positive PD-L1 status. Programmed death-ligand-1 positivity for use of pembrolizumab is defined by immunohistochemistry as a combined positive score (CPS) of ≥ 10 using the Dako 22C33 platform and for atezolizumab as positivity of ≥ 5% tumour-infiltrating immune cells using Ventana SP142. The PD-1 inhibitor pembrolizumab was tested in 370 patients with advanced or metastatic UC ineligible for cisplatin, showing an ORR of 29% and complete remission in 7% of patients [524]. The PD-L1 inhibitor atezolizumab was also evaluated in the same patient population in a phase II trial (n = 119) showing an ORR of 23% with 9% of patients achieving a complete remission; median OS was 15.9 months [525]. The results are difficult to interpret due to the missing control arm and the heterogeneity of the study population with regards to PD-L1 status. The trials IMvigor 130, Keynote 361 and DANUBE all included an experimental arm with immunotherapy alone using atezolizumab, pembrolizumab and durvalumab, respectively [521-523]. The

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results presented so far have not demonstrated a benefit in terms of PFS or OS compared to platinum-based chemotherapy but no subgroup comparisons for cisplatin-unfit patients were analysed. 7.7.2.4.3 Switch maintenance with immunotherapy The JAVELIN Bladder 100 study investigated the impact of switch maintenance with the PD-L1 inhibitor avelumab after initial treatment with platinum-gemcitabine combination [526]. Patients achieving at least stable disease, or better, after 4–6 cycles of platinum-gemcitabine were randomised to avelumab or best supportive care (BSC). Overall survival was the primary endpoint which improved to 21.4 months with avelumab compared to 14.3 months with BSC (HR: 0.69, 95% CI: 0.56–0.86; p < 0.001). Of patients who discontinued BSC and received subsequent treatment 53% received immunotherapy. Grade 3 or higher side effects occurred in 47% of avelumab patients compared to 25% of BSC patients. Immune-related adverse events occurred in 29% of all patients and 7% experienced grade 3 complications which included colitis, pneumonitis, rash, increased liver enzymes, hyperglycaemia, myositis and hypothyroidism. A randomised phase II trial evaluated switch maintenance treatment with pembrolizumab in patients achieving at least stable disease on platinum-based first-line chemotherapy [527]. One hundred and eight patients were randomised to pembrolizumab or placebo. At a median follow-up of 12.9 months (range 0.9–34.5 months), the primary endpoint of PFS was met (5.4 months vs. 3.0 months, HR: 0.65, p = 0.04) but not the secondary endpoint of OS (22 months vs. 18.7 months, HR: 0.91, 95% CI: 0.52–1.59). 7.7.2.5 Treatment of patients unfit for any platinum-based chemotherapy Limited data exists regarding the optimal treatment for this patient population which is characterised by impaired PS (PS > 2) and/or impaired renal function (GFR < 30 mL/min). Historically, the outcome in this patient group has been poor. Often BSC has been chosen instead of systemic therapy. Most trials evaluating alternative treatment options to cisplatinum-based chemotherapy did not focus specifically on this patient population thereby making interpretation of data difficult. The FDA (but not EMA) has approved pembrolizumab and atezolizumab as first-line treatment for patients not fit to receive any platinum-based chemotherapy regardless of PD-L1 status based on the results of two single-arm phase II trials [524, 525]. It has not been reported how many patients in these two studies were unfit for any platinum-based chemotherapy. 7.7.2.6 Non-platinum combination chemotherapy The use of single-agent chemotherapy has been associated with varying response rates. Responses with single agents are usually short-lived, complete responses are rare, and no long-term DFS/OS has been reported. Different combinations of gemcitabine and paclitaxel have been studied as first- and second-line treatments. Apart from severe pulmonary toxicity with a weekly schedule of both drugs, this combination is well tolerated and produces response rates between 38% and 60% in both lines. Non-platinum combination chemotherapy has not been compared to standard platinum-based chemotherapy in RCTs; therefore, it is not recommended for first-line use in platinum-eligible patients [528-535]. 7.7.3 Second-line systemic therapy for metastatic disease 7.7.3.1 Second-line chemotherapy Second-line chemotherapy data are highly variable and mainly derive from small single-arm phase II trials apart from a single randomised phase III study [497]. A reasonable strategy has been to re-challenge former cisplatin-sensitive patients if progression occurred at least six to twelve months after first-line cisplatin-based combination chemotherapy. Second-line response rates of single-agent treatment with paclitaxel (weekly), docetaxel, nab-paclitaxel (nanoparticle albumin-bound) [536] oxaliplatin, ifosfamide, topotecan, pemetrexed, lapatinib, gefitinib and bortezomib have ranged between 0% and 28% in small phase II trials [537-539]. Gemcitabine has also shown response in second-line use but most patients receive this drug as part of their first-line treatment [535]. The paclitaxel/gemcitabine combination has shown response rates of 38–60% in small single-arm studies. No phase III RCT with an adequate comparator arm has been conducted to assess the true value and OS benefit of this second-line combination [489, 533, 540]. Vinflunine, a third-generation vinca alkaloid, was tested in a phase III RCT and compared against BSC in patients progressing after first-line treatment with platinum-containing combination chemotherapy for metastatic disease [541]. The results showed a modest ORR (8.6%), a clinical benefit with a favourable safety profile and a survival benefit in favour of vinflunine, which was, however, only statistically significant in the eligible patient population (not in the ITT population). Vinflunine was approved as second-line treatment in Europe (not in the U.S.). More recently, second-line therapy with PD-1/PD-L1 checkpoint inhibitors has been established as standard second-line

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therapy and vinflunine is reserved for patients with contraindications to immunotherapy and may be considered as third- or later-line treatment option although no randomised data for these indications exist. A randomised phase III trial evaluated the addition of the angiogenesis inhibitor ramucirumab to docetaxel chemotherapy vs. docetaxel alone, which resulted in improved PFS (4.07 vs. 2.76 months) and higher response rates (24.5% vs. 14%), respectively [542]. While the primary endpoint of PFS prolongation was reached, the clinical benefit appears small and no OS benefit has been shown [543]. 7.7.3.2 Second-line immunotherapy for platinum-pre-treated patients The immune checkpoint inhibitors pembrolizumab, nivolumab, atezolizumab, avelumab, and durvalumab have demonstrated similar efficacy and safety in patients progressing during, or after, standard platinum-based chemotherapy in phase I, II and III trials. Pembrolizumab, a PD-1 inhibitor, has been tested in patients progressing during or after platinum-based firstline chemotherapy in a phase III RCT and demonstrated a significant OS benefit leading to approval. In the trial, patients (n = 542) were randomised to receive either pembrolizumab monotherapy or chemotherapy (paclitaxel, docetaxel or vinflunine). The median OS in the pembrolizumab arm was 10.3 months (95% CI: 8.0–11.8) vs. 7.4 months (95% CI: 6.1–8.3) for the chemotherapy arm (HR for death, 0.73, 95% CI: 0.59–0.91, p = 0.002) independent of PD-L1 expression levels [544]. This trial was recently updated with a longer follow-up of 27.7 months showing consistent improvement of OS [545]. In addition, HRQoL analysis showed that patients on pembrolizumab experience stable, or improved, HRQoL, whereas it deteriorated on chemotherapy [546]. Atezolizumab, a PD-L1 inhibitor, tested in patients progressing during, or after, previous platinum-based chemotherapy in phase I, phase II and phase III trials, was the first checkpoint inhibitor approved for BC [204, 547, 548]. The phase III RCT (IMvigor211) included 931 patients comparing atezolizumab with second-line chemotherapy (either paclitaxel, docetaxel or vinflunine) did not meet its primary endpoint of improved OS for patients with high PD-L1 expression (immune cells [IC] score 2/3) with 11.1 months (atezolizumab) vs. 10. 6 (chemotherapy) months (stratified HR: 0.87, 95% CI: 0.63–1.21, p = 0.41) but OS was numerically improved in the ITT population in an exploratory analysis (8.6 months vs. 8.0 months, HR: 0.85, 95% CI: 0.73–0.99). A phase IV single-arm safety study was conducted with atezolizumab including 1,004 patients confirming the efficacy and tolerability profile [549]. The PD-1 inhibitor nivolumab was approved based on the results of a single-arm phase II trial (CheckMate 275), enrolling 270 platinum pre-treated patients. The first endpoint was ORR. Objective response rate was 19.6%, and OS was 8.74 months for the entire group [550]. Based on results of phase I/II and phase IB trials, two additional PD-L1 inhibitors, durvalumab and avelumab, are currently only approved for this indication in the U.S. [551-553]. 7.7.3.2.1 Side-effect profile of immunotherapy Checkpoint inhibitors including PD-1 or PD-L1 antibodies and CTLA-4 antibodies have a distinct side effect profile associated with their mechanism of action leading to enhanced immune system activity. These adverse events can affect any organ in the body leading to mild, moderate or severe side effects. The most common organs affected are the skin, gastrointestinal tract, liver, lung, thyroid, adrenal and pituitary gland. Other systems that may be affected include musculoskeletal, renal, nervous, haematologic, ocular and cardiovascular system. Any change during immunotherapy treatment should raise suspicion about a possible relation to the treatment. The nature of immune-related adverse events has been very well characterised and published [554]. The timely and appropriate treatment of immune-related side effects is crucial to achieve optimal benefit from the treatment while maintaining safety. Clear guidelines for side effect management have been published [555]. Immunotherapy treatment should be applied and supervised by trained clinicians only to ensure early side effect recognition and treatment. In case of interruption of immunotherapy, re-challenge will require close monitoring for adverse events [556]. 7.7.4 Novel agents for second- or later-line therapy Genomic profiling of urothelial carcinoma has revealed common potentially actionable genomic alterations including alterations in FGFR [557]. Erdafitinib is a pan-FGFR tyrosine kinase inhibitor and the first FDAapproved targeted therapy for metastatic urothelial carcinoma with susceptible FGFR2/3 alterations following platinum-containing chemotherapy. The phase II trial of erdafitinib included 99 patients whose tumour harboured an FGFR3 mutation or FGFR2/3 fusion and who had disease progression following chemotherapy [202]. The confirmed ORR was 40% and an additional 39% of patients had stable disease. A total of 22 patients had previously received immunotherapy with only one patient achieving a response, yet the response

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rate for erdafitinib for this subgroup was 59%. At a median follow-up of 24 months, the median PFS was 5.5 months (95% CI: 4.0–6.0) and the median OS was 11.3 months (95% CI: 9.7–15.2) [202]. Treatmentrelated adverse events of ≥ grade 3 occurred in 46% of patients. Common adverse events of ≥ grade 3 were hyponatraemia (11%), stomatitis (10%), and asthenia (7%) and 13 patients discontinued erdafitinib due to adverse events, including retinal pigment epithelial detachment, hand-foot syndrome, dry mouth, and skin/nail events. In addition to erdafitinib, several other FGFR inhibitors are being evaluated including infigratinib which has demonstrated promising activity [203]. The increased identification of FGFR3 mutations/fusion in UTUCs and in NMIBC has led to several ongoing trials. Another promising drug is enfortumab vedotin, an antibody-drug conjugate (ADC) targeting Nectin-4, a cell adhesion molecule which is highly expressed in UC conjugated to monomethyl auristatin E (MMAE). A published phase-II single-arm study (n = 125) in patients previously treated with platinum chemotherapy and checkpoint inhibition showed a confirmed objective response rate of 44%, including 12% complete responses [558]. Responses were seen across patient subgroups including 41% in checkpoint inhibitor non-responders and 38% in patients with liver metastases. The most common treatment-related AEs included fatigue (50%), alopecia (48%), and decreased appetite (41%). Treatment-related AEs of interest included any rash (48% all grade, 11% ≥ G3) and any peripheral neuropathy (50% all grade, 3% ≥ G3). This data led to the accelerated FDA approval for enfortumab vedotin in locally advanced or metastatic UC patients who have previously received a PD-1 or PD-L1 inhibitor, and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting [559]. A phase III RCT comparing enfortumab vedotin with single-agent chemotherapy has reported preliminary results (ASCO GU 2021), reporting a significant survival benefit [558]. Another ongoing trial has reported promising activity for the combination of enfortumab vedotin in combination with pembrolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced/metastatic UC (ORR: 73.3% with 15.6% complete responses) [560]. Another promising ADC is sacituzumab govitecan, targeting trophoblast cell surface antigen 2 (Trop-2) conjugated to SN-38, the active metabolite of irinotecan [561]. 7.7.5 Post-chemotherapy surgery and oligometastatic disease With cisplatin-containing combination chemotherapy, excellent response rates may be obtained in patients with LN metastases only, good PS and adequate renal function, including a high number of complete responses with up to 20% of patients achieving long-term DFS [512, 516, 562, 563]. The role of surgery of residual LNs after chemotherapy is still unclear. Although some studies suggest a survival benefit and QoL improvement, the level of evidence supporting this practice is mainly anecdotal [564-578]. Retrospective studies of post-chemotherapy surgery after partial or complete remission have indicated that surgery may contribute to long-term DFS in selected patients [579-582]. These findings have been confirmed in a recent systematic review including 28 studies [582]. In the absence of data from RCTs, patients should be evaluated on an individual basis and discussed by an interdisciplinary tumour board [582]. 7.7.6 Treatment of patients with bone metastases The prevalence of metastatic bone disease (MBD) in patients with advanced/metastatic UC is 30–40% [583]. Skeletal complications due to MBD have a detrimental effect on pain and QoL and are also associated with increased mortality [584]. Bisphosphonates such as zoledronic acid reduce and delay skeletal-related events (SREs) due to bone metastases by inhibiting bone resorption, as shown in a small pilot study [585]. Denosumab, a fully human monoclonal antibody that binds to and neutralises RANKL (receptor activator of nuclear factor κB ligand), was shown to be non-inferior to zoledronic acid in preventing or delaying SREs in patients with solid tumours and advanced MBD, including patients with UC [586]. Patients with MBD, irrespective of the cancer type, should be considered for bone-targeted treatment [584]. Patients treated with zoledronic acid or denosumab should be informed about possible side effects including osteonecrosis of the jaw and hypocalcaemia. Supplementation with calcium and vitamin D is mandatory. Dosing regimens of zoledronic acid should follow regulatory recommendations and have to be adjusted according to pre-existing medical conditions, especially renal function [587]. For denosumab, no dose adjustments are required for variations in renal function.

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7.7.7

Summary of evidence and guidelines for metastatic disease

Summary of evidence In a first-line setting, performance status (PS) and the presence or absence of visceral metastases are independent prognostic factors for survival. In a second-line setting, negative prognostic factors are: liver metastasis, PS ≥ 1 and low haemoglobin (< 10 g/dL). Cisplatin-containing combination chemotherapy can achieve median survival of up to 14 months, with long-term disease-free survival (DFS) reported in ~15% of patients with nodal disease and good PS. Single-agent chemotherapy provides low response rates of usually short duration. Carboplatin combination chemotherapy is less effective than cisplatin-based chemotherapy in terms of complete response and survival. Non-platinum combination chemotherapy has not been tested against standard chemotherapy in patients who are fit or unfit for cisplatin-combination chemotherapy. There is no defined standard therapy for platinum chemotherapy-unfit patients with advanced or metastatic urothelial cancer (UC). Post-chemotherapy surgery after partial or complete response may contribute to long-term DFS in selected patients. Zoledronic acid and denosumab have been approved for supportive treatment in case of bone metastases of all cancer types including UC, as they reduce and delay skeletal related events. PD-1 inhibitor pembrolizumab has been approved for patients that have progressed during or after previous platinum-based chemotherapy based on the results of a phase III trial. PD-L1 inhibitors atezolizumab, nivolumab, durvalumab and avelumab have been FDA approved for patients that have progressed during or after previous platinum-based chemotherapy based on the results of a phase II trial. PD-1 inhibitor pembrolizumab and PD-L1 inhibitor atezolizumab have been approved for patients with advanced or metastatic UC unfit for cisplatinum-based first-line chemotherapy and with overexpression of PD-L1 based on the results of single-arm phase II trials. The combination of chemotherapy plus pembrolizumab or atezolizumab and the combination of durvalumab and tremelimumab have not demonstrated OS survival benefit compared to platinumbased chemotherapy alone. Switch maintenance with the PD-L1 inhibitor avelumab has demonstrated significant OS benefit in patients achieving at least stable disease on first-line platinum-based chemotherapy. Recommendations First-line treatment for platinum-fit patients Use cisplatin-containing combination chemotherapy with GC or HD-MVAC. In patients unfit for cisplatin but fit for carboplatin use the combination of carboplatin and gemcitabine. In patients achieving stable disease, or better, after first-line platinum-based chemotherapy use maintenance treatment with PD-L1 inhibitor avelumab. First-line treatment in patients unfit for platinum-based chemotherapy Consider checkpoint inhibitors pembrolizumab or atezolizumab. Second-line treatment Offer checkpoint inhibitor pembrolizumab to patients progressing during, or after, platinumbased combination chemotherapy for metastatic disease. If this is not possible, offer atezolizumab, nivolumab (EMA, FDA approved); avelumab or durvalumab (FDA approved). Further treatment after platinum- and immunotherapy Offer treatment in clinical trials testing novel antibody drug conjugates (enfortumab vedotin, sacituzumab govitecan); or in case of patients with FGFR3 alterations, FGFR tyrosine kinase inhibitors.

LE 1b 1b 1b 2a 2a 4 2b 3 1b 1b 2a

2a

1b

1b

Strength rating Strong Strong Strong

Weak Strong

Strong

GC = gemcitabine plus cisplatin; FGFR = fibroblast growth factor receptor; HD-MVAC = high-dose intensity methotrexate, vinblastine, adriamycin plus cisplatin.

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Figure 7.2: Flow chart for the management of metastatic urothelial cancer*

PLATINUM-INELIGIBLE

PLATINUM-ELIGIBLE cisplatin

PS 2 and GFR < 60 mL/min PS > 2; GFR < 30 mL/min

carboplatin

PS 0-1 and GFR > 50-60 mL/min

PS 2 or GFR 30-60 mL/min

cisplatin/gemcitabine or DD-MVAC 4-6 cycles

carboplatin/gemcitabine 4-6 cycles

PD

PD-L1 +

PD-L1 -

CR/PR/SD

2nd line therapy

PD

Watchful waiting

Maintenance

• pembrolizumab (atezolizumab, avelumab, durvalumab, nivolumab) • Trials

Switch maintenance: avelumab

Immunotherapy • atezolizumab • pembrolizumab

Best supportive care

LATER-LINE THERAPY UC patients refractory to platinum-based chemotherapy and IO

FGFR3 mutation UC progressing on platinum-based chemotherapy ± prior IO

• •

•

erdafitinib (FDA) – in trial chemotherapy: o paclitaxel o Docetaxel o vinflunine Trials

• •

•

enfortumab vedotin (FDA) – in trial chemotherapy: o paclitaxel o docetaxel o vinflunine Trials

*Treatment within clinical trials is highly encouraged. BSC = best supportive care; CR = complete response; DD-MVAC = dose dense methotrexate vinblastine doxorubicin cisplatin; EV = enfortumab vedotin; FDA = US Food and Drug Administration; FGFR = pan-fibroblast growth factor receptor tyrosine kinase inhibitor; GFR = glomerular filtration rate; IO = immunotherapy; PR = partial response; PS = performance status; SD = stable disease.

7.8

Quality of life

7.8.1 Introduction The evaluation of HRQoL considers physical, psychological, emotional and social functioning. In patients with MIBC, HRQoL declines in particular in the physical and social functioning domains [588]. Several questionnaires have been validated for assessing HRQoL in patients with BC, including FACT (Functional Assessment of Cancer Therapy)-G [589], EORTC QLQ-C30 [590], EORTC QLQ-BLM (MIBC module) [591], and SF (Short Form)36 [592, 593] and recently the BCI questionnaire specifically designed and validated for BC patients [594]. 7.8.2 Neoadjuvant chemotherapy The impact of NAC on patient-reported outcomes (using EORTC QLQ questionnaires) was investigated by Feuerstein et al. [595]. A propensity-matched analysis of 101 patients who completed NAC and 54 patients who did not undergo NAC, showed no negative effect of NAC on patient-reported outcomes. Similar results were reported by Huddart et al. based on data from the BC2001 trial [466].

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7.8.3 Radical cystectomy and urinary diversion Two systematic reviews and meta-analyses focused on HRQoL after RC and urinary diversion [351, 596]. Yang et al. compared HRQoL of incontinent and continent urinary diversions (all types) including 29 studies (n = 3,754) of which 9 had a prospective design (one of which was randomised) [351]. Only three studies reported HRQoL data both pre- and post-operatively. In these three studies, an initial deterioration in overall HRQoL was reported but general health, functional and emotional domains at 12 months post-surgery were equal or better than baseline. After 12 months, the HRQoL benefits diminished in all domains. Overall, no difference in HRQoL between continent and incontinent urinary diversion was reported although an ileal conduit may confer a small physical health benefit [596]. Cerruto et al. reported HRQoL comparing ileal conduit with orthotopic neobladder reconstruction [596]. A pooled analysis was performed including 18 studies (n = 1,553) of which the vast majority were retrospective studies. The analysis showed no statistical significant difference in overall HRQoL, but methodological limitations need to be considered. Clifford et al. prospectively evaluated continence outcomes in male patients undergoing orthotopic neobladder diversion [597]. Day-time continence increased from 59% at less than three months post-operatively to 92% after 12 to 18 months. Night-time continence increased from 28% at less than three months post-operatively to 51% after 18 to 36 months. Also of interest is the urinary bother in females with an orthotopic neobladder. Bartsch and co-workers reported day-time and night-time continence rates of 70.4% and 64.8%, respectively, in 56 female neobladder patients. Thirty-five patients (62.5%) performed clean intermittent catheterisation, which is much worse when compared to male neobladder patients. Moreover, patients with non-organconfined disease (p = 0.04) and patients with a college degree (p = 0.001) showed worse outcomes on HRQoL scores [598]. Altogether, there is no superior type of urinary diversion in terms of overall HRQoL in unselected patients. Health-related QoL outcomes are most likely a result of good patient selection. An older, more isolated, patient is probably better served with an ileal conduit, whereas a younger patient with a likely higher level of interest in body image and sexuality is better off with an orthotopic diversion. The patient’s choice is the key to the selection of reconstruction method [351]. 7.8.4 Bladder sparing trimodality therapy The only HRQoL data in bladder sparing treatment collected in an RCT setting was published by Huddart et al. [466]. The primary endpoint was the change in the Bladder Cancer Subscale (BLCS), as part of the FACT-BL questionnaire, at one year post-treatment. Questionnaire return rate at one and five years was 70% and 60%, respectively. The remaining patients did mostly not respond as a result of recurrence or RC. The data show a reduction in HRQoL in the majority of the domains immediately following radiotherapy but in most patients the HRQoL scores returned to baseline 6 months after RT and maintained at this level for five years. Approximately 33% of patients reported persistent lower Bladder Cancer Subscale scores after five years. Addition of chemotherapy did not affect the HRQoL outcomes. 7.8.5 Non-curative or metastatic bladder cancer In non-curative or metastatic BC, HRQoL is reduced because of associated micturition problems, bleeding, pain and therefore disturbance of social and sexual life [599]. There is limited literature describing HRQoL in BC patients receiving palliative care [600] but there are reports of bladder-related symptoms relieved by palliative surgery [423], RT [601], and/or chemotherapy [602]. A HRQoL analysis was performed in platinum-refractory patients who were randomised to pembrolizumab vs. another line of chemotherapy (KEYNOTE-45 trial) [546]. It was reported that patients treated with pembrolizumab had stable or improved global health status/QoL, whereas those treated with investigators’ choice of chemotherapy experienced declines in global health [546]. 7.8.6

Summary of evidence and recommendations for health-related quality of life

Summary of evidence Compared to non-cancer controls, the diagnosis and treatment of bladder cancer has a negative impact on HRQoL. There is no significant difference in overall QoL between patients with continent or incontinent diversion. In patients with MIBC treated with RC, overall HRQoL declines immediately after treatment and recovers to baseline at 12 months post-operatively.

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LIMITED UPDATE MARCH 2021

In patients with MIBC treated with radiotherapy, overall HRQoL declines immediately after treatment. 1b In most patients, overall HRQoL then recovers to baseline at 6 months and maintains at this level to 5 years. In patients with MIBC treated with radiotherapy, concomitant chemotherapy or neo-adjuvant 1b chemotherapy has no significant impact on HRQoL. In patients with platinum-refractory advanced urothelial carcinoma, pembrolizumab may be superior in 1b terms of HRQoL compared to another line of chemotherapy. Recommendations Use validated questionnaires to assess health-related quality of life in patients with muscleinvasive bladder cancer. Discuss the type of urinary diversion taking into account a patient preference, existing comorbidities, tumour variables and coping abilities.

8.

FOLLOW-UP

8.1

Follow-up in muscle invasive bladder cancer

Strength rating Strong Strong

An appropriate schedule for disease monitoring should be based on natural timing of recurrence; probability and site of recurrence; functional monitoring after urinary diversion and the potential available management options [603]. Nomograms on CSS following RC have been developed and externally validated, but their wider use cannot be recommended until further data become available [604, 605]. Current surveillance protocols are based on patterns of recurrence drawn from retrospective series only. Combining this data is not possible since most retrospective studies use different follow-up regimens and imaging techniques. Additionally, reports of asymptomatic recurrences diagnosed during routine oncological follow-up and results from retrospective studies are contradictory [606-608]. From the Volkmer B, et al. series of 1,270 RC patients, no differences in OS were observed between asymptomatic and symptomatic recurrences [607]. Conversely, in the Giannarini, et al. series of 479 patients; those with recurrences detected during routine follow-up (especially in the lungs) and with secondary urothelial tumours as the site of recurrence, had a slightly higher survival [606]. Boorjian, et al. included 1,599 RC patients in their series, with 77% symptomatic recurrences. On multivariate analysis, patients who were symptomatic at recurrence had a 60% increased risk of death as compared to asymptomatic patients [608]. However, at this time, no data from prospective trials demonstrating the potential benefit of early detection of recurrent disease and its impact on OS are available [609]. For details see Section 7.5.4.

8.2

Site of recurrence

8.2.1 Local recurrence Local recurrence takes place in the soft tissues of the original surgical site or in LNs. Contemporary cystectomy has a 5–15% probability of pelvic recurrence which usually occurs during the first 24 months, most often within 6 to 18 months after surgery. However, late recurrences can occur up to five years after RC. Risk factors described are pathological stage, LNs, positive margins, extent of LND and peri-operative chemotherapy [610]. Patients generally have a poor prognosis after pelvic recurrence. Even with treatment, median survival ranges from four to eight months following diagnosis. Definitive therapy can prolong survival, but mostly provides significant palliation of symptoms. Trimodality management generally involves a combination of chemotherapy, radiation and surgery [609]. 8.2.2 Distant recurrence Distant recurrence is seen in up to 50% of patients treated with RC for MIBC. As with local recurrence, pathological stage and nodal involvement are risk factors [611]. Systemic recurrence is more common in locally advanced disease (pT3/4), ranging from 32 to 62%, and in patients with LN involvement (range 52–70%) [612]. The most likely sites for distant recurrence are LNs, lungs, liver and bone. Nearly 90% of distant recurrences appear within the first three years after RC, mainly in the first two years, although late recurrence has been described after more than 10 years. Median survival of patients with progressive disease treated with platinum-based chemotherapy is 9–26 months [613-615]. However, longer survival (28–33% at 5 years) has been reported in patients with minimal metastatic disease undergoing trimodality management, including metastasectomy [565, 573].

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8.2.3 Urothelial recurrences After RC, the incidence of new urethral tumours was 4.4% (1.3–13.7%). Risk factors for secondary urethral tumours are urethral malignancy in the prostatic urethra/prostate (in men) and bladder neck (in women). Orthotopic neobladder was associated with a significant lower risk of urethral tumours after RC (OR: 0.44) [616]. There is limited data, and agreement, about urethral follow-up, with some authors recommending routine surveillance with urethral wash and urine cytology and others doubting the need for routine urethral surveillance. However, there is a significant survival advantage in men with urethral recurrence diagnosed asymptomatically vs. symptomatically, so follow-up of the male urethra is indicated in patients at risk of urethral recurrence [609]. Treatment is influenced by local stage and grade of urethral occurrence. In urethral CIS, BCG instillations have success rates of 83% [617]. In invasive disease, urethrectomy should be performed if the urethra is the only site of disease; in case of distant disease, systemic chemotherapy is indicated [3]. Upper urinary tract UCs occur in 4–10% of cases and represent the most common sites of late recurrence (3-year DFS following RC) [618]. Median OS is 10–55 months, and 60–67% of patients die of metastatic disease [609]. A meta-analysis found that 38% of UTUC recurrence was diagnosed by follow-up investigations, whereas in the remaining 62%, diagnosis was based on symptoms. When urine cytology was used during surveillance, the rate of primary detection was 7% vs. 29.6% with UUT imaging. The meta-analysis concluded that patients with non-invasive cancer are twice as likely to have UTUC as patients with invasive disease [619]. Multifocality increases the risk of recurrence by three-fold, while positive ureteral or urethral margins increase the risk by seven-fold. Radical nephroureterectomy can prolong survival [620].

8.3

Time schedule for surveillance

Although, based on low level evidence only, some follow-up schedules have been suggested, guided by the principle that recurrences tend to occur within the first years following initial treatment. A schedule suggested by the EAU Guidelines Panel includes a CT scan (every 6 months) until the third year, followed by annual imaging thereafter. Patients with multifocal disease, NMIBC with CIS or positive ureteral margins are at higher risk of developing UTUC, which can develop late (> 3 years). In those cases, monitoring of the UUT is mandatory during follow-up. Computed tomography is to be used for imaging of the UUT [619]. The exact time to stop follow-up is not well known and recently a risk-adapted schedule has been proposed, based on the interaction between recurrence risk and competing health factors that could lead to individualised recommendations and may increase recurrence detection. Elderly and very low-risk patients (those with NMIBC or pT0 disease at final cystectomy report) showed a higher competing risk of non-BC mortality when compared with their level of BC recurrence risk. On the other hand, patients with locally advanced disease or LN involvement are at a higher risk of recurrence for more than 20 years [621]. However, this model has not been validated and does not incorporate several risk factors related to non-BC mortality. Furthermore, the prognostic implications of the different sites of recurrence should be considered. Local and systemic recurrences have a poor prognosis and early detection of the disease will not influence survival [622]. Despite this, the rationale for a risk-adapted schedule for BC surveillance appears to be promising and deserves further investigation. Since data for follow-up strategies are sparse, a number of key questions were included in a recently held consensus project [8, 9]. Outcomes for all statements for which consensus was achieved are listed in Section 8.6.

8.4

Follow-up of functional outcomes and complications

Apart from oncological surveillance, patients with a urinary diversion need functional follow-up. Complications related to urinary diversion are detected in 45% of patients during the first five years of follow-up. This rate increases over time, and exceeds 54% after 15 years of follow-up. In a single-centre series of 259 male patients, long-term follow-up after orthotopic bladder substitution (median 121 months [range 60–267]), showed that excellent long-term functional outcomes can be achieved in high-volume centres with dedicated teams [623]. A smaller multi-centre series including women only (n = 102) showed complication rates between 5–12% after orthotopic neobladder (median follow up of 24 months [range 1.5–100 months]). Both early (5%) and late (12%) complications related to the urinary diversion [624]. The functional complications are diverse and include: vitamin B12 deficiency, metabolic acidosis, worsening of renal function, urinary infections, urolithiasis, stenosis of uretero-intestinal anastomosis, stoma complications in patients with ileal conduit, neobladder continence problems, and emptying dysfunction [609]. Functional complications are especially common in women: approximately two-thirds need to catheterise their neobladder, while almost 45% do not void spontaneously at all [598]. There seems to be a correlation between

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voiding patterns and nerve preservation; in 66 women bilateral preservation of autonomic nerves decreased the need for catheterisation to between 3.4–18.7% (CI: 95%) [624]. Recently a 21% increased risk of fractures was also described as compared to no RC due to chronic metabolic acidosis and subsequent long-term bone loss [622]. Since low vitamin B12 levels have been reported in 17% of patients with bowel diversion, in case of cystectomy and bowel diversion, vitamin B12 levels should be measured annually [8, 9, 378].

8.5

Summary of evidence and recommendations for specific recurrence sites

Site of recurrence Local recurrence

Distant recurrence

Upper urinary tract recurrence Secondary urethral tumour

8.6

Summary of evidence Poor prognosis. Treatment should be individualised depending on the local extent of tumour. Poor prognosis.

Recommendation Offer radiotherapy, chemotherapy and possibly surgery as options for treatment, either alone or in combination. Offer chemotherapy as the first option, and consider metastasectomy or radiotherapy in case of unique metastasis site. See EAU Guidelines on Upper Urinary Tract Urothelial Carcinomas.

Risk factors are multifocal disease (NMIBC/CIS or positive ureteral margins). Staging and treatment should See EAU Guidelines on Primary Urethral Carcinoma. be done as for primary urethral tumour.

Strength rating Strong

Strong

Strong

Strong

EAU-ESMO consensus statements on the management of advanced- and variant bladder cancer [8, 9]*

Consensus statement After radical cystectomy with curative intent, regular follow-up is needed. After radical cystectomy with curative intent, follow-up for the detection of second cancers in the urothelium is recommended. After radical cystectomy with curative intent, follow-up of the urethra with cytology and/or cystoscopy is recommended in selected patients (e.g., multifocality, carcinoma in situ and tumour in the prostatic urethra). After trimodality treatment with curative intent, follow-up for the detection of relapse is recommended every 3–4 mos initially; then after 3 yrs, every 6 mos in the majority of patients. After trimodality treatment with curative intent, regular follow-up for the detection of relapse is needed in the majority of patients. After trimodality treatment with curative intent, follow-up imaging to assess distant recurrence or recurrence outside the bladder is needed. After trimodality treatment with curative intent, assessment of the urothelium to detect recurrence is recommended every 6 mos in the majority of patients. After trimodality treatment with curative intent, in addition to a CT scan, other investigations of the bladder are recommended. In patients with a partial or complete response after chemotherapy for metastatic urothelial cancer, regular follow-up is needed. Imaging studies may be done according to signs/symptoms. To detect relapse (outside the bladder) after trimodality treatment with curative intent, CT of the thorax and abdomen is recommended as the imaging method for follow-up in the majority of patients. To detect relapse (outside the bladder) after trimodality treatment with curative intent, routine imaging with CT of the thorax and abdomen should be stopped after 5 yrs in the majority of patients. In patients treated with radical cystectomy with curative intent and who have a neobladder, management of acid bases household includes regular measurements of pH and sodium bicarbonate substitution according to the measured value. To detect relapse after radical cystectomy with curative intent, routine imaging with CT of the thorax and abdomen should be stopped after 5 yrs in the majority of patients.

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To detect relapse after radical cystectomy with curative intent, a CT of the thorax and abdomen is recommended as the imaging method for follow-up in the majority of patients. Levels of LDH and CEA are not essential in the follow-up of patients with urothelial cancer to detect recurrence. Vitamin B12 levels have to be measured annually in the follow-up of patients treated with radical cystectomy and bowel diversion with curative intent. *Only statements which met the a priori consensus threshold across all three stakeholder groups are listed (defined as ≥ 70% agreement and ≤ 15% disagreement, or vice versa). CEA = carcinoembryonic antigen; CT = computed tomography; LDH = lactate dehydrogenase; mos = months; yrs = years.

9.

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Malkowicz, S.B., et al. Muscle-invasive urothelial carcinoma of the bladder. Urology, 2007. 69: 3. https://pubmed.ncbi.nlm.nih.gov/17280906 Karakiewicz, P.I., et al. Nomogram for predicting disease recurrence after radical cystectomy for transitional cell carcinoma of the bladder. J Urol, 2006. 176: 1354. https://pubmed.ncbi.nlm.nih.gov/16952631 Zaak, D., et al. Predicting individual outcomes after radical cystectomy: an external validation of current nomograms. BJU Int, 2010. 106: 342. https://pubmed.ncbi.nlm.nih.gov/20002664 Giannarini, G., et al. Do patients benefit from routine follow-up to detect recurrences after radical cystectomy and ileal orthotopic bladder substitution? Eur Urol, 2010. 58: 486. https://pubmed.ncbi.nlm.nih.gov/20541311 Volkmer, B.G., et al. Oncological followup after radical cystectomy for bladder cancer-is there any benefit? J Urol, 2009. 181: 1587. https://pubmed.ncbi.nlm.nih.gov/19233433 Boorjian, S.A., et al. Detection of asymptomatic recurrence during routine oncological followup after radical cystectomy is associated with improved patient survival. J Urol, 2011. 186: 1796. https://pubmed.ncbi.nlm.nih.gov/21944088 Soukup, V., et al. Follow-up after surgical treatment of bladder cancer: a critical analysis of the literature. Eur Urol, 2012. 62: 290. https://pubmed.ncbi.nlm.nih.gov/22609313 Huguet, J. Follow-up after radical cystectomy based on patterns of tumour recurrence and its risk factors. Actas Urol Esp, 2013. 37: 376. https://pubmed.ncbi.nlm.nih.gov/23611464 Ghoneim, M.A., et al. Radical cystectomy for carcinoma of the bladder: 2,720 consecutive cases 5 years later. J Urol, 2008. 180: 121. https://pubmed.ncbi.nlm.nih.gov/18485392 Donat, S.M. Staged based directed surveillance of invasive bladder cancer following radical cystectomy: valuable and effective? World J Urol, 2006. 24: 557. https://pubmed.ncbi.nlm.nih.gov/17009050 Mathers, M.J., et al. Is there evidence for a multidisciplinary follow-up after urological cancer? An evaluation of subsequent cancers. World J Urol, 2008. 26: 251. https://pubmed.ncbi.nlm.nih.gov/18421461 Vrooman, O.P., et al. Follow-up of patients after curative bladder cancer treatment: guidelines vs. practice. Curr Opin Urol, 2010. 20: 437. https://pubmed.ncbi.nlm.nih.gov/20657286 Cagiannos, I., et al. Surveillance strategies after definitive therapy of invasive bladder cancer. Can Urol Assoc J, 2009. 3: S237. https://pubmed.ncbi.nlm.nih.gov/20019993 Fahmy, O., et al. Urethral recurrence after radical cystectomy for urothelial carcinoma: A systematic review and meta-analysis. Urol Oncol, 2018. 36: 54. https://pubmed.ncbi.nlm.nih.gov/29196179 Varol, C., et al. Treatment of urethral recurrence following radical cystectomy and ileal bladder substitution. J Urol, 2004. 172: 937. https://pubmed.ncbi.nlm.nih.gov/15311003 Gakis, G., et al. Systematic Review on the Fate of the Remnant Urothelium after Radical Cystectomy. Eur Urol, 2017. 71: 545. https://pubmed.ncbi.nlm.nih.gov/27720534 Picozzi, S., et al. Upper urinary tract recurrence following radical cystectomy for bladder cancer: a meta-analysis on 13,185 patients. J Urol, 2012. 188: 2046. https://pubmed.ncbi.nlm.nih.gov/23083867 Sanderson, K.M., et al. Upper tract urothelial recurrence following radical cystectomy for transitional cell carcinoma of the bladder: an analysis of 1,069 patients with 10-year followup. J Urol, 2007. 177: 2088. https://pubmed.ncbi.nlm.nih.gov/17509294 Stewart-Merrill, S.B., et al. Evaluation of current surveillance guidelines following radical cystectomy and proposal of a novel risk-based approach. Urol Oncol, 2015. 33: 339 e1. https://pubmed.ncbi.nlm.nih.gov/26031371 Gupta, A., et al. Risk of fracture after radical cystectomy and urinary diversion for bladder cancer. J Clin Oncol, 2014. 32: 3291. https://pubmed.ncbi.nlm.nih.gov/25185104

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623.

624.

Hautmann, R.E., et al. Functional Outcome and Complications following Ileal Neobladder Reconstruction in Male Patients without Tumor Recurrence. More than 35 Years of Experience from a Single Center. J Urol, 2021. 205: 174. https://pubmed.ncbi.nlm.nih.gov/32856988 Stenzl, A., et al. Urethra-sparing cystectomy and orthotopic urinary diversion in women with malignant pelvic tumors. Cancer, 2001. 92: 1864. https://pubmed.ncbi.nlm.nih.gov/11745259

10. CONFLICT OF INTEREST All members of the Muscle-invasive and Metastatic Bladder Cancer Guidelines Working Group have provided disclosure statements of all relationships that they have that might be perceived as a potential source of a conflict of interest. This information is publicly accessible through the European Association of Urology website: https://uroweb.org/guideline/bladder-cancer-muscle-invasive-and-metastatic/?type=panel. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organization and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

11. CITATION INFORMATION The format in which to cite the EAU Guidelines will vary depending on the style guide of the journal in which the citation appears. Accordingly, the number of authors or whether, for instance, to include the publisher, location, or an ISBN number may vary. The compilation of the complete Guidelines should be referenced as: EAU Guidelines. Edn. presented at the EAU Annual Congress Milan 2021. ISBN 978-94-92671-13-4. If a publisher and/or location is required, include: EAU Guidelines Office, Arnhem, The Netherlands. http://uroweb.org/guidelines/compilations-of-all-guidelines/ References to individual guidelines should be structured in the following way: Contributors’ names. Title of resource. Publication type. ISBN. Publisher and publisher location, year.

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EAU Guidelines on

Upper Urinary Tract Urothelial Carcinoma M. Rouprêt, M. Babjuk (Chair), M. Burger (Vice-chair), E. Compérat, N.C. Cowan, P. Gontero, F. Liedberg, A. Masson-Lecomte, A.H. Mostafid, J. Palou, B.W.G. van Rhijn, S.F. Shariat, R. Sylvester Guidelines Associates: O. Capoun, D. Cohen, J.L. Dominguez-Escrig, T. Seisen, V. Soukup

© European Association of Urology 2021

TABLE OF CONTENTS

PAGE

1. INTRODUCTION 1.1 Aim and scope 1.2 Panel composition 1.3 Available publications 1.4 Publication history & summary of changes 1.4.1 Summary of changes

4 4 4 4 4 4

2.

5 5 6

METHODS 2.1 Data identification 2.2 Review

3. EPIDEMIOLOGY, AETIOLOGY AND PATHOLOGY 3.1 Epidemiology 3.2 Risk factors 3.3 Histology and classification 3.3.1 Histological types 3.4 Summary of evidence and recommendations for epidemiology, aetiology and pathology

6 6 7 8 8 8

4.

8 8 9 9 9

STAGING AND CLASSIFICATION SYSTEMS 4.1 Classification 4.2 Tumour Node Metastasis staging 4.3 Tumour grade 4.4 Future developments

5. DIAGNOSIS 5.1 Symptoms 5.2 Imaging 5.2.1 Computed tomography urography 5.2.2 Magnetic resonance urography 5.3 Cystoscopy 5.4 Cytology 5.5 Diagnostic ureteroscopy 5.6 Distant metastases 5.6.1 18F-Fluorodeoxglucose positron emission tomography/computed tomography 5.7 Summary of evidence and guidelines for the diagnosis of UTUC

9 9 9 9 10 10 10 10 10 10 11

6. PROGNOSIS 6.1 Prognostic factors 6.1.1 Patient-related factors 6.1.1.1 Age and gender 6.1.1.2 Ethnicity 6.1.1.3 Tobacco consumption 6.1.1.4 Surgical delay 6.1.1.5 Other factors 6.1.2 Tumour-related factors 6.1.2.1 Tumour stage and grade 6.1.2.2 Tumour location, multifocality, size and hydronephrosis 6.1.2.3 Variant histology 6.1.2.4 Lymph node involvement 6.1.2.5 Lymphovascular invasion 6.1.2.6 Surgical margins 6.1.2.7 Other pathological factors 6.1.3 Molecular markers 6.2 Risk stratification for clinical decision making 6.2.1 Low- versus high-risk UTUC 6.2.2 Peri-operative predictive tools for high-risk disease 6.3 Bladder recurrence 6.4 Summary of evidence and guidelines for the prognosis of UTUC

11 11 11 11 11 11 11 11 12 12 12 12 12 12 12 12 12 12 12 13 14 14

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7. DISEASE MANAGEMENT 7.1 Localised non-metastatic disease 7.1.1 Kidney-sparing surgery 7.1.1.1 Ureteroscopy 7.1.1.2 Percutaneous access 7.1.1.3 Ureteral resection 7.1.1.4 Upper urinary tract instillation of topical agents 7.1.1.5 Guidelines for kidney-sparing management of UTUC 7.1.2 Management of high-risk non-metastatic UTUC 7.1.2.1 Surgical approach 7.1.2.1.1 Open radical nephroureterectomy 7.1.2.1.2 Minimal invasive radical nephroureterectomy 7.1.2.1.3 Management of bladder cuff 7.1.2.1.4 Lymph node dissection 7.1.3 Peri-operative chemotherapy 7.1.3.1 Neoadjuvant chemotherapy 7.1.3.2 Adjuvant chemotherapy 7.1.4 Adjuvant radiotherapy after radical nephroureterectomy 7.1.5 Post-operative bladder instillation 7.1.6 Summary of evidence and guidelines for the management of high-risk nonmetastatic UTUC 7.2 Metastatic disease 7.2.1 Radical nephroureterectomy 7.2.2 Metastasectomy 7.2.3 Systemic treatments 7.2.3.1 First-line setting 7.2.3.2 Second-line setting 7.2.4 Summary of evidence and guidelines for the treatment of metastatic UTUC

17 20 20 20 20 20 20 21

8.

FOLLOW-UP 8.1 Summary of evidence and guidelines for the follow-up of UTUC

22 22

9.

REFERENCES

23

10.

CONFLICT OF INTEREST

38

11.

CITATION INFORMATION

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14 14 14 14 14 15 15 15 15 15 15 15 16 16 16 16 16 16 17

3

1.

INTRODUCTION

1.1

Aim and scope

The European Association of Urology (EAU) Non-muscle-invasive Bladder Cancer (NMIBC) Guidelines Panel has compiled these clinical guidelines to provide urologists with evidence-based information and recommendations for the management of upper urinary tract urothelial carcinoma (UTUC). Separate EAU guidelines documents are available addressing non-muscle-invasive bladder cancer [1], muscle-invasive and metastatic bladder cancer (MIBC) [2], and primary urethral carcinoma [3]. It must be emphasised that clinical guidelines present the best evidence available to the experts but following guideline recommendations will not necessarily result in the best outcome. Guidelines can never replace clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions - also taking personal values and preferences/individual circumstances of patients into account. Guidelines are not mandates and do not purport to be a legal standard of care.

1.2

Panel composition

The European Association of Urology (EAU) Guidelines Panel on NMIBC consists of an international multidisciplinary group of clinicians, including urologists, uro-oncologists, a radiologist, a pathologist and a statistician. Members of this panel have been selected based on their expertise and to represent the professionals treating patients suspected of harbouring urothelial carcinoma (UC). All experts involved in the production of this document have submitted potential conflict of interest statements, which can be viewed on the EAU website Uroweb: https://uroweb.org/guideline/upper-urinary-tract-urothelial-cell-carcinoma/.

1.3

Available publications

A quick reference document (Pocket guidelines) is available in print and as an app for iOS and Android devices, presenting the main findings of the UTUC Guidelines. These are abridged versions which may require consultation together with the full text version. Several scientific publications are available as are a number of translations of all versions of the EAU UTUC Guidelines, the most recent scientific summary was published in 2020 [4]. All documents are accessible through the EAU website Uroweb: https://uroweb.org/guideline/upperurinary-tract-urothelial-cell-carcinoma/.

1.4

Publication history & summary of changes

The first EAU Guidelines on UTUC were published in 2011. This 2021 publication presents a substantial update of the 2020 version. 1.4.1 Summary of changes The literature for the complete document has been assessed and updated, whenever relevant. Conclusions and recommendations have been rephrased and added to throughout the current document. Key changes for the 2021 print: • Chapter 5 – Diagnosis, new section 5.3 – 18F-Fluorodeoxglucose positron emission tomography/ computed tomography (FDT-PET/CT) was added resulting in a change of a recommendation. 5.7 Summary of evidence and guidelines for the diagnosis of UTUC Recommendation Magnetic resonance urography or FDG-PET/CT may be used when CT is contraindicated.

•

Strength rating Weak

Chapter 6 – Prognosis, additional information has been addeded and this section was restructured, resulting in changes to Figures 6.1 and 6.2 and the Summary of evidence. New sections 6.2.2 – Perioperative predictive tools for high risk disease and 6.3 – Bladder recurrence were added. 6.4 Summary of evidence and guidelines for the prognosis of UTUC Summary of evidence Models are available to predict non-organ confined disease and altered prognosis after RNU. Patient, tumour and treatment-related factors impact risk of bladder recurrence.

4

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•

Chapter 7 – Treatment, Sections 7.1.2 – Management of high-risk non-metastatic UTUC and 7.1.3.3 – Induction chemotherapy were added. Section 7.1.5 – Post-operative bladder instillation was expanded, resulting in a changed recommendation. 7.1.6 Summary of evidence and guidelines for the management of high-risk non-metastatic UTUC Summary of evidence Post-operative chemotherapy improves disease-free survival. Recommendation Offer post-operative systemic platinum-based chemotherapy to patients with muscle-invasive UTUC.

•

LE 1b Strength rating Strong

Section 7.2 – Metastatic disease, systemic treatments, considerable new data has been added in both the first-line and second-line setting, not resulting in a change to the recommendations. A change was made to Figure 7.2 – Surgical treatment according to location and status, to include post-operative chemotherapy as an option for high-risk tumours.

2.

METHODS

2.1

Data identification

Standard procedure for EAU Guidelines includes an annual assessment of newly published literature in the field to guide future updates. For the 2021 UTUC Guidelines, new and relevant evidence has been identified, collated and appraised through a structured assessment of the literature. The search was restricted to articles published between May 30th 2019 and May 29th 2020. Databases searched included Pubmed, Ovid, EMBASE and both the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews. After deduplication, a total of 614 unique records were identified, retrieved and screened for relevance. Excluded from the search were basic research studies, case series, reports and editorial comments. Only articles published in the English language, addressing adults were included. The publications identified were mainly retrospective, including some large multicentre studies. Owing to the scarcity of randomised data, articles were selected based on the following criteria: evolution of concepts, intermediate- and long-term clinical outcomes, study quality, and relevance. Older studies were only included if they were historically relevant. A total of 35 new publications were added to the 2021 UTUC Guidelines print. A detailed search strategy is available online: https://uroweb.org/guideline/upper-urinary-tract-urothelial-cell-carcinoma/?type=appendicespublications. For Chapters 3-6 (Epidemiology, Aetiology and Pathology, Staging and Classification systems, Diagnosis and Prognosis) references used in this text are assessed according to their level of evidence (LE) based on the 2009 Oxford Centre for Evidence-Based Medicine (CEBM) Levels of Evidence [5]. For the Disease Management and Follow-up chapters (Chapters 7 and 8) a system modified from the 2009 CEBM LEs has been used [5]. For each recommendation within the guidelines there is an accompanying online strength rating form, based on a modified GRADE methodology [6, 7]. These forms address a number of key elements, namely: 1. 2. 3. 4. 5. 6.

 he overall quality of the evidence which exists for the commendation references used in T this text are graded according to the CEBM Levels of Evidence (see above) [5]; the magnitude of the effect (individual or combined effects); the certainty of the results (precision, consistency, heterogeneity and other statistical or study related factors); the balance between desirable and undesirable outcomes; the impact of patient values and preferences on the intervention; the certainty of those patient values and preferences.

These key elements are the basis which panels use to define the strength rating of each recommendation. The strength of each recommendation is represented by the words ‘strong’ or ‘weak’. The strength of each recommendation is determined by the balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including certainty of estimates), and nature and variability of patient values and preferences [8].

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Additional information can be found in the general Methodology section of this print, and online at the EAU website; https://uroweb.org/guidelines/policies-and-methodological-documents/. A list of Associations endorsing the EAU Guidelines can also be viewed online at the above address.

2.2

Review

The 2021 UTUC Guidelines have been peer-reviewed prior to publication.

3.

EPIDEMIOLOGY, AETIOLOGY AND PATHOLOGY

3.1

Epidemiology

Urothelial carcinomas (UCs) are the sixth most common tumours in developed countries [9]. They can be located in the lower (bladder and urethra) and/or the upper (pyelocaliceal cavities and ureter) urinary tract. Bladder tumours account for 90–95% of UCs and are the most common urinary tract malignancy [1]. Upper urinary tract UCs are uncommon and account for only 5–10% of UCs [9] with an estimated annual incidence in Western countries of almost two cases per 100,000 inhabitants. This rate has risen in the past few decades as a result of improved detection and improved bladder cancer survival [10]. Pyelocaliceal tumours are approximately twice as common as ureteral tumours and multifocal tumours are found in approximately 10–20% of cases [11]. The presence of concomitant carcinoma in situ of the upper tract is between 11 and 36% [10]. In 17% of cases, concurrent bladder cancer is present [12] whilst a prior history of bladder cancer is found in 41% of American men but in only 4% of Chinese men [13]. This, along with genetic and epigenetic factors, may explain why Asian patients present with more advanced and higher grade disease compared to other ethnic groups [10]. Following treatment, recurrence in the bladder occurs in 22–47% of UTUC patients, depending on initial tumour grade [14] compared with 2–5% in the contralateral upper tract [15]. With regards to UTUC occurring following an initial diagnosis of bladder cancer, a series of 82 patients treated with bacillus Calmette-Guérin (BCG) who had regular upper tract imaging between years 1 and 3 showed a 13% incidence of UTUC, all of which were asymptomatic [16], whilst in another series of 307 patients without routine upper tract imaging the incidence was 25% [17]. A multicentre cohort study (n = 402) with a 50 month follow-up has demonstrated a UTUC incidence of 7.5% in NMIBC receiving BCG with predictors being intravesical recurrence and non-papillary tumour at transurethral resection of the bladder [18]. Following radical cystectomy for MIBC, 3–5% of patients develop a metachronous UTUC [19, 20]. Approximately two-thirds of patients who present with UTUCs have invasive disease at diagnosis compared to 15–25% of patients presenting with muscle-invasive bladder tumours [21]. This is probably due to the absence of muscularis propria layer in the upper tract, so tumours are more likely to upstage at an earlier time-point. Approximately 9% of patients present with metastasis [10, 22]. Upper urinary tract UCs have a peak incidence in individuals aged 70–90 years and are twice as common in men [23]. Upper tract UC and bladder cancer exhibit significant differences in the prevalence of common genomic alterations. In individual patients with a history of both tumours, bladder cancer and UTUC were always clonally related. Genomic characterisation of UTUC provides information regarding the risk of bladder recurrence and can identify tumours associated with Lynch syndrome [24]. The Amsterdam criteria are a set of diagnostic criteria used by doctors to help identify families which are likely to have Lynch syndrome [25]. In Lynch-related UTUC, immunohistochemistry analysis showed loss of protein expression corresponding to the disease-predisposing MMR (mismatch repair) gene mutation in 98% of the samples (46% were microsatellite instable and 54% microsatellite stable) [26]. The majority of tumours develop in MSH2 mutation carriers [26]. Patients identified at high risk for Lynch syndrome should undergo DNA sequencing for patient and family counselling [27, 28]. Germline mutations in DNA MMR genes defining Lynch syndrome, are found in 9% of patients with UTUC compared to 1% of patients with bladder cancer, linking UTUC to Lynch syndrome [29]. A study of 115 consecutive UTUC patients, reported that 13.9% screened positive for potential Lynch syndrome and 5.2% had confirmed Lynch syndrome [30]. This is one of the highest rates of undiagnosed genetic disease in urological cancers, which justifies screening of all patients under 65 presenting with UTUC and those with a family history of UTUC (see Figure 3.1) [31, 32].

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Figure 3.1: S  election of patients with UTUC for Lynch syndrome screening during the first medical Interview

UTUC

Systemac screening during medical interview

Suspicion of hereditary UTUC - Age < 65 yr - Personal history of Lynch-spectrum cancer or - First-degree relave < 50 yr with Lynch-spectrum cancer or - Two first-degree relaves with Lynch-spectrum cancer

Sporadic UTUC

Germ-line DNA sequencing: mutaon (5-9%)

- Clinical evaluaon for other Lynch-related cancer: colorectal, gastrointesnal, endometrial ovarian and skin - Close monitoring and follow-up - Familial genec counselling UTUC = upper urinary tract urothelial carcinoma.

3.2

Risk factors

A number of environmental factors have been implicated in the development of UTUC [11, 33]. Published evidence in support of a causative role for these factors is not strong, with the exception of smoking and aristolochic acid. Tobacco exposure increases the relative risk of developing UTUC from 2.5 to 7.0 [34-36]. A large population-based study assessing familial clustering in relatives of UC patients, including 229,251 relatives of case subjects and 1197,552 relatives of matched control subjects, has demonstrated genetic or environmental roots independent of smoking-related behaviours. With more than 9% of the cohort being UTUC patients, clustering was not seen in upper tract disease. This may suggest that the familial clustering of urothelial cancer is specific to lower tract cancers [37]. In Taiwan, the presence of arsenic in drinking water has been tentatively linked to UTUC [38]. Aristolochic acid, a nitrophenanthrene carboxylic acid produced by Aristolochia plants, exerts multiple effects on the urinary system. Aristolochic acid irreversibly injures renal proximal tubules resulting in chronic tubulointerstitial disease, while the mutagenic properties of this chemical carcinogen lead predominantly to UTUC [39-41]. Aristolochic acid has been linked to bladder cancer, renal cell carcinoma, hepatocellular carcinoma and intrahepatic cholangiocarcinoma [42]. Two routes of exposure to aristolochic acid are known: (i) environmental contamination of agricultural products by Aristolochia plants, as reported for Balkan endemic nephropathy [43]; and (ii) ingestion of Aristolochia-based herbal remedies [44, 45]. Aristolochia herbs are used worldwide, especially in China and Taiwan [41]. Following bioactivation, aristolochic acid reacts with genomic DNA to form aristolactam-deoxyadenosine adducts [46]; these lesions persist for decades in target tissues, serving as robust biomarkers of exposure [9]. These adducts generate a unique mutational spectrum,

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7

characterised by A>T transversions located predominately on the non-transcribed strand of DNA [42, 47]. However, fewer than 10% of individuals exposed to aristolochic acid develop UTUC [40]. Two retrospective series found that aristolochic acid-associated UTUC is more common in females [48, 49]. However, females with aristolochic acid UTUC have a better prognosis than their male counterparts. Alcohol consumption is associated with development of UTUC. A large case-control study (1,569 cases and 506,797 controls) has evidenced a significantly higher risk of UTUC in ever-drinkers compared to neverdrinkers (OR: 1.23; 95% CI: 1.08–1.40, p = 0.001). Compared to never-drinkers, the risk threshold for UTUC was > 15 g of alcohol/day. A dose-response was observed [50]. Differences in the ability to counteract carcinogens may contribute to host susceptibility to UTUC. Some genetic polymorphisms are associated with an increased risk of cancer or faster disease progression that introduces variability in the inter-individual susceptibility to the risk factors previously mentioned. Upper urinary tract UCs may share some risk factors and described molecular pathways with bladder UC [24]. So far, two UTUC-specific polymorphisms have been reported [51]. A history of bladder cancer is associated with higher risk of UTUCs (see Section 3.1). Patients who undergo ureteral stenting prior to radical cystectomy are at higher risk for upper tract recurrence [52].

3.3

Histology and classification

3.3.1 Histological types Upper urinary tract tumours are almost always urothelial carcinomas and pure non-urothelial histology is rare [53, 54]. However, variants are present in approximately 25% of UTUCs [55, 56]. Pure squamous cell carcinoma of the urinary tract is often assumed to be associated with chronic inflammatory diseases and infections arising from urolithiasis [57, 58]. Urothelial carcinoma with divergent squamous differentiation is present in approximately 15% of cases [57]. Keratinising squamous metaplasia of urothelium is a risk factor for squamous cell cancers and therefore mandates surveillance. Upper urinary tract UCs with variant histology are highgrade and have a worse prognosis compared with pure UC [56, 59, 60]. Other variants, although rare, include sarcomatoid and UCs with inverted growth [60]. However, collecting duct carcinomas, which may seem to share similar characteristics with UCs, display a unique transcriptomic signature similar to renal cancer, with a putative cell of origin in the distal convoluted tubules. Therefore, collecting duct carcinomas are considered as renal tumours [61].

3.4

Summary of evidence and recommendations for epidemiology, aetiology and pathology

Summary of evidence Aristolochic acid and smoking exposure increases the risk for UTUC. Patients with Lynch syndrome are at risk for UTUC.

LE 2a 3

Recommendations Strength rating Evaluate patient and family history based on the Amsterdam criteria to identify patients with Weak upper tract urothelial carcinoma. Evaluate patient exposure to smoking and aristolochic acid. Weak

4.

STAGING AND CLASSIFICATION SYSTEMS

4.1

Classification

The classification and morphology of UTUC and bladder carcinoma are similar [1]. However, it is not possible to distinguish between non-invasive papillary tumours (papillary urothelial tumours of low malignant potential and low- and high-grade papillary UC) [62], flat lesions (carcinoma in situ [CIS]), and invasive carcinoma. This is in most cases due to the size of biopsy specimens that do not include deep tissue required for pathological staging. With UTUC, histological grade is a surrogate for pathological stage, as it strongly correlates [63].

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4.2

Tumour Node Metastasis staging

The tumour, node, metastasis (TNM) classification is shown in Table 1 [64]. The regional lymph nodes (LNs) are the hilar and retroperitoneal nodes and, for the mid- and distal ureter, the pelvic nodes. Laterality does not affect N classification.

4.3

Tumour grade

In 2004, the WHO and the International Society of Urological Pathology published a new histological classification of UCs which provides a different patient stratification between individual categories compared to the older 1973 WHO classification [65, 66]. In 2016, an update of the 2004 WHO grading classification was published without major changes [65]. These guidelines are still based on both the 1973 and 2004/2016 WHO classifications since most published data use the 1973 classification [62].

4.4

Future developments

A number of studies focussing on molecular classification have been able to demonstrate genetically different groups of UTUC by evaluating DNA, RNA and protein expression. Four molecular subtypes with distinct clinical behaviours were identified, but, as yet, it is unclear whether these subtypes will respond differently to treatment [67]. Table 1: TNM classification 2017 for upper tract urothelial cell carcinoma [64] T - Primary tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour Ta Non-invasive papillary carcinoma Tis Carcinoma in situ T1 Tumour invades subepithelial connective tissue T2 Tumour invades muscularis T3 (Renal pelvis) Tumour invades beyond muscularis into peripelvic fat or renal parenchyma (Ureter) Tumour invades beyond muscularis into periureteric fat T4 Tumour invades adjacent organs or through the kidney into perinephric fat N - Regional lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single lymph node 2 cm or less in the greatest dimension N2 Metastasis in a single lymph node more than 2 cm, or multiple lymph nodes M - Distant metastasis M0 No distant metastasis M1 Distant metastasis TNM = Tumour, Node, Metastasis (classification).

5.

DIAGNOSIS

5.1

Symptoms

The diagnosis of UTUC may be incidental or symptom related. The most common symptom is visible or nonvisible haematuria (70–80%) [68, 69]. Flank pain, due to clot or tumour tissue obstruction or less often due to local growth, occurs in approximately 20–32% of cases [69, 70]. Systemic symptoms (including anorexia, weight loss, malaise, fatigue, fever, night sweats, or cough) associated with UTUC should prompt evaluation for metastases associated with a worse prognosis [70].

5.2

Imaging

5.2.1 Computed tomography urography Computed tomography (CT) urography has the highest diagnostic accuracy of the available imaging techniques [71]. A meta-analysis of 13 studies comprising 1,233 patients revealed a pooled sensitivity of CT urography for UTUC of 92% (CI: 0.85–0.96) and a pooled specificity of 95% (CI: 0.88–0.98) [72].

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Rapid acquisition of thin sections allows high-resolution isotropic images that can be viewed in multiple planes to assist with diagnosis without loss of resolution. Epithelial “flat lesions” without mass effect or urothelial thickening are generally not visible with CT. The presence of enlarged LNs is highly predictive of metastases in UTUC [73, 74]. 5.2.2 Magnetic resonance urography Magnetic resonance (MR) urography is indicated in patients who cannot undergo CT urography, usually when radiation or iodinated contrast media are contraindicated [75]. The sensitivity of MR urography is 75% after contrast injection for tumours < 2 cm [75]. The use of MR urography with gadolinium-based contrast media should be limited in patients with severe renal impairment (< 30 mL/min creatinine clearance), due to the risk of nephrogenic systemic fibrosis. Computed tomography urography is more sensitive and specific for the diagnosis and staging of UTUC as compared with MR urography [76].

5.3

Cystoscopy

Urethrocystocopy is an integral part of UTUC diagnosis to rule out concomitant bladder cancer [10, 12].

5.4

Cytology

Abnormal cytology may indicate high-grade UTUC when bladder cystoscopy is normal, and in the absence of CIS in the bladder and prostatic urethra [1, 77, 78]. Cytology is less sensitive for UTUC than bladder tumours and should be performed selectively for the affected upper tract [79]. In a recent study, barbotage cytology detected up to 91% of cancers [80]. Barbotage cytology taken from the renal cavities and ureteral lumina is preferred before application of a contrast agent for retrograde ureteropyelography as it may cause deterioration of cytological specimens [81]. Retrograde ureteropyelography remains an option to detect UTUCs [71, 82, 83]. The sensitivity of fluorescence in situ hybridisation (FISH) for molecular abnormalities characteristic of UTUCs is approximately 50% and therefore its use in clinical practice remains unproven [84, 85].

5.5

Diagnostic ureteroscopy

Flexible ureteroscopy (URS) is used to visualise the ureter, renal pelvis and collecting system and for biopsy of suspicious lesions. Presence, appearance and size of tumour can be determined using URS. In addition, ureteroscopic biopsies can determine tumour grade in more than 90% of cases with a low false-negative rate, regardless of sample size [86]. Undergrading may occur following diagnostic biopsy, making intensive follow-up necessary if kidney-sparing treatment is chosen [87]. Ureteroscopy also facilitates selective ureteral sampling for cytology in situ [83, 88, 89]. Stage assessment using ureteroscopic biopsy is inaccurate. Combining ureteroscopic biopsy grade, imaging findings such as hydronephrosis, and urinary cytology may help in the decision-making process between radical nephroureterectomy (RNU) and kidneysparing therapy [89, 90]. While some studies suggest a higher rate of intravesical recurrence after RNU in patients who underwent diagnostic URS pre-operatively [91, 92], one study did not [93]. Technical developments in flexible ureteroscopes and the use of novel imaging techniques improve visualisation and diagnosis of flat lesions [94]. Narrow-band imaging is a promising technique, but results are preliminary [95]. Optical coherence tomography and confocal laser endomicroscopy (Cellvizio®) have been used in vivo to evaluate tumour grade and/or for staging purposes, with a promising correlation with definitive histology in high-grade UTUC [96, 97]. Recommendations for the diagnosis of UTUC are listed in Section 5.6.

5.6

Distant metastases

Prior to any treatment with curative intent, it is essential to rule out distant metastases. Computed tomography is the diagnostic technique of choice for lung- and abdominal staging for metastases [72]. 18F-Fluorodeoxglucose positron emission tomography/computed tomography 5.6.1 A retrospective multi-centre publication on the use of 18F-Fluorodeoxglucose positron emission tomography/ computed tomography (FDG-PET/CT) for the detection of nodal metastasis in 117 surgically-treated UTUC patients reported a promising sensitivity and specificity of 82% and 84%, respectively. Suspicious LNs on FDG-PET/CT were associated with worse recurrence-free survival [98]. These results warrant further validation and comparison to MR and CT.

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5.7

Summary of evidence and guidelines for the diagnosis of UTUC

Summary of evidence The diagnosis and staging of UTUC is best done with computed tomography urography and URS. Selective urinary cytology has high sensitivity in high-grade tumours, including carcinoma in situ. Urethrocystoscopy can detect concomitant bladder cancer.

Recommendations Perform a urethrocystoscopy to rule out bladder tumour. Perform a computed tomography (CT) urography for diagnosis and staging. Use diagnostic ureteroscopy and biopsy if imaging and cytology are not sufficient for the diagnosis and/or risk-stratification of the tumour. Magnetic resonance urography or 18F-Fluorodeoxglucose positron emission tomography/ computed tomography may be used when CT is contra-indicated.

6.

PROGNOSIS

6.1

Prognostic factors

LE 2a 3 2a

Strength rating Strong Strong Strong Weak

Upper urinary tract UCs that invade the muscle wall usually have a very poor prognosis. The 5-year specific survival is < 50% for pT2/pT3 and < 10% for pT4 UTUC [99-102]. Many prognostic factors have been identifed and can be used to risk-stratify patients in order to decide on the most appropriate local treatment (radical vs. conservative) and discuss peri-operative systemic therapy. Factors can be divided into patient-related factors and tumour-related factors. 6.1.1 Patient-related factors 6.1.1.1 Age and gender Older age at the time of RNU is independently associated with decreased cancer-specific survival (CSS) [100, 103, 104] (LE: 3). However, even elderly patients can be cured with RNU [105]. Therefore, chronological age alone should not be a contraindication to RNU [104, 105]. Gender has no impact on prognosis of UTUC [23, 100, 106]. 6.1.1.2 Ethnicity One multicentre study of academic centres did not show any difference in outcomes between races [107], but U.S. population-based studies have indicated that African-American patients have worse outcomes than other ethnicities (LE: 3). Whether this is related to access to care or biological and/or patterns of care remains unknown. Another study has demonstrated differences between Chinese and American patients at presentation (risk factor, disease characteristics and predictors of adverse oncologic outcomes) [13]. 6.1.1.3 Tobacco consumption Being a smoker at diagnosis increases the risk for disease recurrence and mortality after RNU [108, 109] and recurrence within the bladder [110] (LE: 3). There is a close relationship between tobacco consumption and prognosis [111] (LE: 3); smoking cessation improves cancer control [109]. 6.1.1.4 Surgical delay A delay between diagnosis of an invasive tumour and its removal may increase the risk of disease progression. Once a decision regarding RNU has been made, the procedure should be carried out within twelve weeks, when possible [112-116] (LE: 3). 6.1.1.5 Other factors A higher American Society of Anesthesiologists score confers worse CSS after RNU [117] (LE: 3), as does poor performance status [118]. Obesity and higher body mass index adversely affect cancer-specific outcomes in patients treated with RNU [119] (LE: 3), with potential differences between races [120]. Several blood-based biomarkers have been associated with locally advanced disease and cancer-specific mortality such as high pre-treatment-derived neutrophil-lymphocyte ratio [121-124], low albumin [123, 125], high C-reactive protein [123] or modified Glasgow score [126], high De Ritis (AST/ALT) ratio [127], altered renal function [123, 128] and high fibrinogen [123, 129] (LE: 3).

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6.1.2 Tumour-related factors 6.1.2.1 Tumour stage and grade The main prognostic factors are tumour stage and grade [21, 89, 100, 130, 131]. 6.1.2.2 Tumour location, multifocality, size and hydronephrosis Initial location of the UTUC is a prognostic factor in some studies [132, 133] (LE: 3). After adjustment for the effect of tumour stage, patients with ureteral and/or multifocal tumours seem to have a worse prognosis than patients diagnosed with renal pelvic tumours [100, 132-138]. Hydronephrosis is associated with advanced disease and poor oncological outcome [73, 81, 139]. A large multi-institutional retrospective study including 932 RNUs for non-metastatic UTUC demonstrated that a 2 cm cut-off appears to be most useful in identifying patients at risk of harbouring ≥ pT2 UTUC [140]. 6.1.2.3 Variant histology Pathological variants are associated with worse cancer-specific and overall survival (OS) [56] (LE: 3). Most studied variants are micropapillary [59], squamous [141] and carcomatoid [59] which are consistently associated with locally advanced disease and worse outcome. 6.1.2.4 Lymph node involvement Patients with nodal metastasis experience very poor survival after surgery [142]. Lymph node density (cut-off 30%) and extranodal extension are powerful predictors of survival outcomes in N+ UTUC [143-145]. Lymph node dissection (LND) performed at the time of RNU allows for optimal tumour staging, although its curative role remains controversial [102, 144, 146, 147] (LE: 3). 6.1.2.5 Lymphovascular invasion Lymphovascular invasion (LVI) is present in approximately 20% of UTUCs and is an independent predictor of survival [148-150]. Lymphovascular invasion status should be specifically reported in the pathological reports of all UTUC specimens [148, 151, 152] (LE: 3). 6.1.2.6 Surgical margins Positive soft tissue surgical margin is associated with a higher disease recurrence after RNU. Pathologists should look for and report positive margins at the level of ureteral transection, bladder cuff, and around the tumour [153] (LE: 3). 6.1.2.7 Other pathological factors Extensive tumour necrosis (> 10% of the tumour area) is an independent prognostic predictor in patients who undergo RNU [154, 155] (LE: 3). In case neoadjuvant treatment was administered, pathological downstaging is associated with better OS [156] (LE: 3). The architecture of UTUC is also a strong prognosticator with sessile growth pattern being associated with worse outcome [157, 158] (LE: 3). Concomitant CIS in organ-confined UTUC and a history of bladder CIS are associated with a higher risk of recurrence and cancer-specific mortality [159, 160] (LE: 3). Macroscopic infiltration or invasion of peri-pelvic adipose tissue confers a higher risk of disease recurrence after RNU compared to microscopic infiltration of renal parenchyma [55, 161]. 6.1.3 Molecular markers Because of the rarity of UTUC, the main limitations of molecular studies are their retrospective design and, for most studies, small sample size. None of the investigated markers have been validated yet to support their introduction in daily clinical decision making [100, 162].

6.2

Risk stratification for clinical decision making

6.2.1 Low- versus high-risk UTUC As tumour stage is difficult to assess clinically in UTUC, it is useful to “risk stratify” UTUC between lowand high risk of progression to identify those patients who are more likely to benefit from kidney-sparing treatment and those who should be treated radically [163, 164] (see Figure 6.2). The factors to consider for risk stratification are presented in Figure 6.1.

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Figure 6.1: Risk stratification of non-metastatic UTUC

UTUC

High-risk UTUC**

Low-risk UTUC*

• • • • •

• • • • • • •

Unifocal disease Tumour size < 2 cm Negave for high-grade cytology Low-grade URS biopsy No invasive aspect on CT

•

Mulfocal disease Tumour size ≥ 2 cm High-grade cytology High-grade URS biopsy Local invasion on CT Hydronephrosis Previous radical cystectomy for highgrade bladder cancer Variant histology

CT = computed tomography; URS = ureteroscopy; UTUC = upper urinary tract urothelial carcinoma. * All these factors need to be present. **Any of these factors need to be present. 6.2.2 Peri-operative predictive tools for high-risk disease There are several pre-RNU models aiming at predicting which patient has muscle-invasive/non-organconfined disease [165-168] (LE: 3). Prognostic nomograms based on pre-operative factors and pathological characteristics are available [102, 168-174]. The main factors included in these models, which may be used when counselling patients regarding follow-up and administration of peri-operative chemotherapy, are detailed in Figure 6.2. Figure 6.2: U  pper urinary tract urothelial cell carcinoma - prognostic factors included in prognostic models

High-risk UTUC

Prognosc factors

Post-operave

Pre-operave

• • • • • • • •

Advanced age Poor social status Chronic kidney disease Ureteral tumour locaon Sessile tumor architecture Advanced clinical stage High grade (biopsy, cytology) Blood based biomarkers

• • • • • •

Advanced stage High grade Carcinoma in situ Lymphovascular invasion Lymph node involvement Sessile tumour architecture

UTUC = upper tract urothelial carcinoma.

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6.3

Bladder recurrence

A meta-analysis of available data has identified significant predictors of bladder recurrence after RNU [175] (LE: 3). Three categories of predictors for increased risk of bladder recurrence were identified: 1. Patient-specific factors such as male gender, previous bladder cancer, smoking and preoperative chronic kidney disease. 2. Tumour-specific factors such as positive pre-operative urinary cytology, tumour grade, ureteral location, multifocality, tumour diameter, invasive pT stage, and necrosis [176]. 3. Treatment-specific factors such as laparoscopic approach, extravesical bladder cuff removal, and positive surgical margins [175]. In addition, the use of diagnostic URS has been associated with a higher risk of developing bladder recurrence after RNU [91, 92] (LE: 3). Based on low-level evidence only, a single dose of intravesical chemotherapy after diagnostic/therapeutic ureteroscopy of non-metastatic UTUC has been suggested to lower the rate of intravesical recurrence, similarly to that after RNU [175].

6.4

Summary of evidence and guidelines for the prognosis of UTUC

Summary of evidence Important prognostic factors for risk stratification include tumour multifocality, size, stage, grade, hydronephrosis and variant histology. Models are available to predict non-organ confined disease and altered prognosis after RNU. Patient, tumour and treatment-related factors impact risk of bladder recurrence. Currently, no prognostic biomarkers are validated for clinical use. Recommendation Use prognostic factors to risk-stratify patients for therapeutic guidance.

7.

DISEASE MANAGEMENT

7.1

Localised non-metastatic disease

LE 3 3 3 3

Strength rating Weak

7.1.1 Kidney-sparing surgery Kidney-sparing surgery for low-risk UTUC reduces the morbidity associated with radical surgery (e.g., loss of kidney function), without compromising oncological outcomes [177]. In low-risk cancers, it is the preferred approach as survival is similar to that after RNU [177]. This option should therefore be discussed in all lowrisk cases, irrespective of the status of the contralateral kidney. In addition, it can also be considered in select patients with a serious renal insufficiency or having a solitary kidney (LE: 3). Recommendations for kidneysparing management of UTUC are listed in Section 7.1.1.5. 7.1.1.1 Ureteroscopy Endoscopic ablation should be considered in patients with clinically low-risk cancer [178, 179]. A flexible ureteroscope is useful in the management of pelvicalyceal tumours [180]. The patient should be informed of the need and be willing to comply with an early second-look URS [181] and stringent surveillance; complete tumour resection or destruction is necessary [181]. Nevertheless, a risk of disease progression remains with endoscopic management due to the suboptimal performance of imaging and biopsy for risk stratification and tumour biology [182]. 7.1.1.2 Percutaneous access Percutaneous management can be considered for low-risk UTUC in the renal pelvis [179, 183] (LE: 3). This may also be offered for low-risk tumours in the lower caliceal system that are inaccessible or difficult to manage by flexible URS. However, this approach is being used less due to the availability of improved endoscopic tools such as distal-tip deflection of recent ureteroscopes [179, 183]. Moreover, a risk of tumour seeding remains with a percutaneous access [183].

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7.1.1.3 Ureteral resection Segmental ureteral resection with wide margins provides adequate pathological specimens for staging and grading while preserving the ipsilateral kidney. Lymphadenectomy can also be performed during segmental ureteral resection [177]. Segmental resection of the proximal two-thirds of ureter is associated with higher failure rates than for the distal ureter [184, 185] (LE: 3). Distal ureterectomy with ureteroneocystostomy are indicated for low-risk tumours in the distal ureter that cannot be removed completely endoscopically and for high-risk tumours when kidney-sparing surgery for renal function preservation is desired (in case of an imperative indication) [101, 184, 185] (LE: 3). A total ureterectomy with an ileal-ureteral substitution is technically feasible, but only in selected cases when a renalsparing procedure is mandatory and the tumour is low risk [186]. 7.1.1.4 Upper urinary tract instillation of topical agents The antegrade instillation of BCG or mitomycin C in the upper urinary tract via percutaneous nephrostomy after complete tumour eradication has been studied for CIS after kidney-sparing management [160, 187] (LE: 3). Retrograde instillation through a single J open-ended ureteric stent is also used. Both the antegrade and retrograde approach can be dangerous due to possible ureteric obstruction and consecutive pyelovenous influx during instillation/perfusion. The reflux obtained from a double-J stent has been used but this approach is suboptimal because the drug often does not reach the renal pelvis [188-191]. A systematic review and meta-analysis assessing the oncologic outcomes of patients with papillary UTUC or CIS of the upper tract treated with kidney-sparing surgery and adjuvant endocavitary treatment analysed the effect of adjuvant therapies (i.e., chemotherapeutic agents and/or immunotherapy with BCG) after kidney-sparing surgery for papillary non-invasive (Ta-T1) UTUCs and of adjuvant BCG for the treatment of upper tract CIS, finding no difference between the method of drug administration (antegrade vs. retrograde vs. combined approach) in terms of recurrence, progression, CSS, and OS. Furthermore, the recurrence rates following adjuvant instillations are comparable to those reported in the literature in untreated patients, questioning their efficacy [192]. The analyses were based on retrospective small studies suffering from publication and reporting bias. A single-arm phase III RCT showed that the use of mitomycin-containing reverse thermal gel (UGN-101) instillations via retrograde catheter to the renal pelvis and calyces was associated with a complete response rate in a total of 42 patients (59%) in biopsy-proven low-grade UTUC measuring less than 15 mm. The median follow-up of patients with a complete response was 11 months. The most frequently reported all-cause adverse events were ureteric stenosis in 31 (44%) of 71 patients, urinary tract infection in 23 (32%), haematuria in 22 (31%), flank pain in 21 (30%), and nausea in 17 (24%). A total of 19 (27%) of 71 patients had drug-related or procedure-related serious adverse events. No deaths were regarded as related to treatment [193]. 7.1.1.5

Guidelines for kidney-sparing management of UTUC

Recommendations Offer kidney-sparing management as primary treatment option to patients with low-risk tumours. Offer kidney-sparing management (distal ureterectomy) to patients with high-risk tumours limited to the distal ureter. Offer kidney-sparing management to patients with solitary kidney and/or impaired renal function, providing that it will not compromise survival. This decision will have to be made on a case-by-case basis in consultation with the patient.

Strength rating Strong Weak Strong

7.1.2 Management of high-risk non-metastatic UTUC 7.1.2.1 Surgical approach 7.1.2.1.1 Open radical nephroureterectomy Open RNU with bladder cuff excision is the standard treatment of high-risk UTUC, regardless of tumour location [21] (LE: 3). Radical nephroureterectomy must be performed according to oncological principles preventing tumour seeding [21]. Section 7.1.6 lists the recommendations for RNU. 7.1.2.1.2 Minimal invasive radical nephroureterectomy Retroperitoneal metastatic dissemination and metastasis along the trocar pathway following manipulation of large tumours in a pneumoperitoneal environment have been reported in few cases [194, 195]. Several precautions may lower the risk of tumour spillage:

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1. 2. 3. 4. 5.

avoid entering the urinary tract; avoid direct contact between instruments and the tumour; perform the procedure in a closed system. Avoid morcellation of the tumour and use an endobag for tumour extraction; the kidney and ureter must be removed en bloc with the bladder cuff; Invasive or large (T3/T4 and/or N+/M+) tumours are contraindications for minimal-invasive RNU as the outcome is worse compared to an open approach [196, 197].

Laparoscopic RNU is safe in experienced hands when adhering to strict oncological principles. There is a tendency towards equivalent oncological outcomes after laparoscopic or open RNU [195, 198-201] (LE: 3). One prospective randomised study has shown that laparoscopic RNU is inferior to open RNU for nonorgan confined UTUC. However, this was a small trial (n = 80), which was likely underpowered [197] (LE: 2). Oncological outcomes after RNU have not changed significantly over the past three decades despite staging and surgical refinements [202] (LE: 3). A robot-assisted laparoscopic approach can be considered with recent data suggesting oncologic equivalence with the other approaches [203-205]. 7.1.2.1.3 Management of bladder cuff Resection of the distal ureter and its orifice is performed because there is a considerable risk of tumour recurrence in this area and in the bladder [175, 184, 206-208]. Several techniques have been considered to simplify distal ureter resection, including the pluck technique, stripping, transurethral resection of the intramural ureter, and intussusception. None of these techniques has convincingly been shown to be equal to complete bladder cuff excision [15, 206, 207] (LE: 3). 7.1.2.1.4 Lymph node dissection The use of a LND template is likely to have a greater impact on patient survival than the number of removed LNs [209]. Template-based and completeness of LND improves CSS in patients with muscle-invasive disease and reduces the risk of local recurrence [210]. Even in clinically [211] and pathologically [212] node-negative patients, LND improves survival. The risk of LN metastasis increases with advancing tumour stage [146]. Lymph node dissection appears to be unnecessary in cases of TaT1 UTUC because of the low risk of LN metastasis [213-216], however, tumour staging is inaccurate pre-operatively; therefore a template-based LND should be offered to all patients who are scheduled for RNU. The templates for LND have been described [210, 217, 218]. 7.1.3 Peri-operative chemotherapy 7.1.3.1 Neoadjuvant chemotherapy In patients treated prior to losing their renal reserve several retrospective studies evaluating the role of neoadjuvant chemotherapy have shown promising pathological downstaging and complete response rates [156, 219-222]. In addition, neoadjuvant chemotherapy has been shown to result in lower disease recurrence and mortality rates compared to RNU alone without compromising the use of definitive surgical treatment [221, 223-225]. No RCTs have been published yet but prospective data from a phase II trial showed that the use of neoadjuvant chemotherapy was associated with a 14% pathological complete response rate for highgrade UTUC [226]. In addition, final pathological stage was ≤ ypT1 in more than 60% of included patients with acceptable toxicity profile. 7.1.3.2 Adjuvant chemotherapy A phase III prospective randomised trial (n = 261) evaluating the benefit of adjuvant gemcitabine-platinum combination chemotherapy initiated within 90 days after RNU vs. surveillance has reported a significant improvement in disease-free survival in patients with pT2–pT4, N (any) or LN-positive (pT any, N1–3) M0 UTUC [227] (LE: 1). The main limitation of using adjuvant chemotherapy for advanced UTUC remains the limited ability to deliver full dose cisplatin-based regimen after RNU, given that this surgical procedure is likely to impact renal function [228, 229]. In a retrospective study histological variants of UTUC exhibit different survival rates and adjuvant chemotherapy was only associated with an OS benefit in patients with pure urothelial carcinoma [230] (LE: 3). 7.1.4 Adjuvant radiotherapy after radical nephroureterectomy Adjuvant radiation therapy has been suggested to control loco-regional disease after surgical removal. The data remains controversial and insufficient for conclusions [232-235]. Moreover, its added value to chemotherapy remains questionable [234].

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7.1.5 Post-operative bladder instillation The rate of bladder recurrence after RNU for UTUC is 22–47% [164, 207]. Two prospective randomised trials [236, 237] and two meta-analyses [238, 239] have demonstrated that a single post-operative dose of intravesical chemotherapy (mitomycin C, pirarubicin) 2–10 days after surgery reduces the risk of bladder tumour recurrence within the first years post-RNU (LE: 2). Prior to instillation, a cystogram might be considered in case of any concerns about drug extravasation. Based on current evidence it is unlikely that additional instillations beyond one peri-operative instillation of chemotherapy further substantially reduces the risk of intravesical recurrence [240]. Whilst there is no direct evidence supporting the use of intravesical instillation of chemotherapy after kidney-sparing surgery, singledose chemotherapy might be effective in that setting as well (LE: 4). Management is outlined in Figures 7.1 and 7.2. One low-level evidence study suggested that bladder irrigation might reduce the risk of bladder recurrence after RNU [241]. 7.1.6

Summary of evidence and guidelines for the management of high-risk non-metastatic UTUC

Summary of evidence Radical nephroureterectomy is the standard treatment for high-risk UTUC, regardless of tumour location. Open, laparoscopic and robotic approaches have similar oncological outcomes for organ-confined UTUC. Failure to completely remove the bladder cuff increases the risk of bladder cancer recurrence. Lymphadenectomy improves survival in muscle-invasive UTUC. Post-operative chemotherapy improves disease-free survival. Single post-operative intravesical instillation of chemotherapy lowers the bladder cancer recurrence rate. Recommendations Perform radical nephroureterectomy (RNU) in patients with high-risk non-metastatic upper tract urothelial carcinoma (UTUC). Perform open RNU in non-organ confined UTUC. Remove the bladder cuff in its entirety. Perform a template-based lymphadenectomy in patients with muscle-invasive UTUC. Offer post-operative systemic platinum-based chemotherapy to patients with muscleinvasive UTUC. Deliver a post-operative bladder instillation of chemotherapy to lower the intravesical recurrence rate.

UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021

LE 2a 2a 3 3 1b 1

Strength rating Strong Weak Strong Strong Strong Strong

17

Figure 7.1: Proposed flowchart for the management of UTUC

UTUC

Diagnosc evaluaon: CTU, urinary cytology, cystoscopy

+/- Flexible ureteroscopy with biopsies

High-risk UTUC*

Low-risk UTUC

RNU +/- template lymphadenectomy +/- peri-operave planum-based combinaon chemotherapy Kidney-sparing surgery: flexible ureteroscopy or segmental resecon or percutaneous approach

Open

(prefer open in cT3, cN+)

Laparoscopic

Recurrence

Close and stringent follow-up

Single post-operave dose of intravesical chemotherapy

*In patients with solitary kidney, consider a more conservative approach. CTU = computed tomography urography; RNU = radical nephroureterectomy; UTUC = upper urinary tract urothelial carcinoma.

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UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021

1. URS 2. Ureteroureterostomy*

Low-risk

Low-risk

1. URS or 2. Distal ureterectomy

High-risk

• RNU +/- LND +/- perioperave chemo

Mid & Proximal

Ureter

Distal

1. RNU or 2. Distal ureterectomy +/- LND +/- perioperave chemo

High-risk

UTUC

1. URS 2. RNU*

Low-risk

Calyx

• RNU +/- LND +/- postoperave chemo

High-risk

Low-risk

High-risk

• RNU +/- LND +/- postoperave chemo

Renal pelvis

1. URS 2. Percutaneous

Kidney

Figure 7.2: Surgical treatment according to location and risk status

1 = first treatment option; 2 = secondary treatment option. *In case not amendable to endoscopic management. LND = lymph node dissection; RNU = radical nephroureterectomy; URS = ureteroscopy; UTUC = upper urinary tract urothelial carcinoma.

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7.2

Metastatic disease

7.2.1 Radical nephroureterectomy The role of RNU in the treatment of patients with metastatic UTUC has recently been explored in several observational studies [242-245]. Although evidence remains very limited, RNU may be associated with cancerspecific [242, 244, 245] and OS benefit in selected patients, especially those fit enough to receive cisplatinbased chemotherapy [243, 244]. It is noteworthy that these benefits may be limited to those patients with only one metastatic site [244]. Nonetheless, given the high risk of bias of the observational studies addressing RNU for metastatic UTUC, indications for RNU in this setting should mainly be reserved for palliative patients, aimed at controlling symptomatic disease [17, 108] (LE: 3). 7.2.2 Metastasectomy There is no UTUC-specific study supporting the role of metastasectomy in patients with advanced disease. However, several reports including both UTUC and bladder cancer patients suggested that resection of metastatic lesions could be safe and oncologically beneficial in selected patients with a life expectancy of more than six months [246-248]. This was confirmed in the most recent and largest study to date [249]. Nonetheless, in the absence of data from randomised controlled trials, patients should be evaluated on an individual basis and the decision to perform a metastasectomy (surgically or otherwise) should be done in a shared decisionmaking process with the patient. 7.2.3 Systemic treatments 7.2.3.1 First-line setting Extrapolating from the bladder cancer literature and small, single-centre, UTUC studies, platinum-based combination chemotherapy, especially using cisplatin, is likely to be efficacious as first-line treatment of metastatic UTUC. A retrospective analysis of three RCTs showed that primary tumour location in the lower- or upper urinary tract had no impact on progression-free or OS in patients with locally advanced or metastatic UC treated with platinum-based combination chemotherapy [250]. The efficacy of immunotherapy using programmed death-1 (PD1) or programmed death-ligand 1 (PD-L1) inhibitors has been evaluated in the first-line setting for the treatment of patients with metastactic urothelial carcinoma, including those with UTUC. Data from a phase III RCT showed that the use of avelumab maintenance therapy after 4 to 6 cycles of gemcitabin plus cisplatin or carboplatin significantly prolonged OS as compared to best supportive care alone in those patients with advanced or metastatic urothelial carcinoma who did not progress during, or responded to, first-line chemotherapy [251]. Although no subgroup analysis based on tumour location was available in this study, almost 30% of the included patients had UTUC. Atezolizumab was associated with an objective response rate of 39% in 33 (28%) cisplatin-ineligible patients with metastatic UTUC included in a single-arm phase II trial (n = 119) [252]. Median OS in the overall cohort was 15.9 months and toxicity was acceptable. However, data from a phase III RCT including 1,213 patients with metastatic urothelial carcinoma, of which 312 (26%) were diagnosed with UTUC patients showed that the combination of atezolizumab with platinum-based chemotherapy was associated with limited PFS benefit as compared to platinum-based chemotherapy alone and no significant impact was observed on OS. In a single-arm phase II trial (n = 370) pembrolizumab was associated with an objective response rate of 22% in 69 (19%) cisplatin-ineligible patients with metastatic UTUC [253]. In the overall cohort, a PD-L1 expression of 10% was associated with a greater response rate to pembrolizumab, which had acceptable toxicity. However, addition of pembrolizumab to platinum-based chemotherapy did not reach statistical significance for PFS and OS benefits as compared to platinum-based chemotherapy alone in a phase III RCT in 351 patients with metastatic urothelial carcinoma including 64 (18%) UTUC patients [254]. Another negative phase III RCT showed that durvalumab alone, or in combination with tremelimumab, did not prolong OS as compared to platinum-based chemotherapy for metastatic urothelial carcinoma [255]. This study included 221 (21%) UTUC patients and subgroup analyses suggested that durvalumab alone may have better efficacy for these individuals as compared to those with bladder cancer. No other data are currently available in the first-line setting but several trials are currently testing immunotherapy combinations with nivolumab (NCT03036098 [256]), pembrolizumab (NCT02178722 [257]) or durvalumab (NCT03682068 [258]) in patients with metastatic UC, including those with UTUC. 7.2.3.2 Second-line setting Similar to the bladder cancer setting, second-line treatment of metastatic UTUC remains challenging. In a post-hoc subgroup analysis of locally advanced or metastatic UC, vinflunine was reported to be as effective in UTUC as for bladder cancer progressing after cisplatin-based chemotherapy [259]. 20

UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021

More importantly, a phase III RCT including 542 patients who received prior platinum-based chemotherapy for advanced UC showed that pembrolizumab could decrease the risk of death by almost 50% in those with UTUC (n = 75, 13.8%), although these results were borderline significant [260]. The objective response rate was 21.1% in the overall cohort and median OS was 10.3 months. Interestingly, although no subgroup analysis was available for UTUC patients (n = 65/21%), a single-arm phase II trial demonstrated that atezolizumab has durable activity associated with PD-L1 expression on immune cells in patients with metastatic UC [261]. The objective response rate was 26% in the group of those overexpressing PD-L1 and 15% in the overall population. However, a phase III RCT, including 51 (21.8%) patients with UTUC, showed that it was not associated with prolonged OS as compared to chemotherapy in patients overexpressing PD-L1, despite a more favourable safety profile [262]. Other immunotherapies such as nivolumab [263], avelumab [264, 265] and durvalumab [266] have shown objective response rates ranging from 17.8% [266] to 19.6% [263] and median OS ranging from 7.7 months to 18.2 months in patients with platinum-resistant metastatic UC, overall. These results were obtained from single-arm phase I or II trials only and the number of UTUC patients included in these studies was only specified for avelumab (n = 7/15.9%) [265] without any subgroup analysis based on primary tumour location. The immunotherapy combination of nivolumab plus ipilimumab has shown significant anti-tumour activity with objective response rate up to 38% in a phase I/II multicentre trial including 78 patients with metastatic UC progressing after platinum-based chemotherapy [267]. Although UTUC patients were included in this trial, no subgroup analysis was available. Other immunotherapy combinations may be effective in the second-line setting but data are currently limited [268]. In a recent phase II study the use of erdafitinib, a tyrosine kinase inhibitor of FGFR1-4, was associated with a 40% response rate in 99 patients with metastatic urothelial carcinoma and prespecified FGFR alterations who progressed after first-line chemotherapy [269]. This study included 23 UTUC patients with visceral metastases showing a 43% response rate. 7.2.4

Summary of evidence and guidelines for the treatment of metastatic UTUC

Summary of evidence Radical nephroureterectomy may improve quality of life and oncologic outcomes in select metastatic patients. Cisplatin-based combination chemotherapy can improve median survival. Single-agent and carboplatin-based combination chemotherapy are less effective than cisplatin-based combination chemotherapy in terms of complete response and survival. Non-platinum combination chemotherapy has not been tested against standard chemotherapy in patients who are fit or unfit for cisplatin combination chemotherapy. PD-1 inhibitor pembrolizumab has been approved for patients who have progressed during or after previous platinum-based chemotherapy based on the results of a phase III trial. PD-L1 inhibitor atezolizumab has been FDA approved for patients that have progressed during or after previous platinum-based chemotherapy based on the results of a phase II trial. PD-1 inhibitor nivolumab has been approved for patients that have progressed during or after previous platinum-based chemotherapy based on the results of a phase II trial. PD-1 inhibitor pembrolizumab has been approved for patients with advanced or metastatic UC ineligible for cisplatin-based first-line chemotherapy based on the results of a phase II trial but use of pembrolizumab is restricted to PD-L1 positive patients. PD-L1 inhibitor atezolizumab has been approved for patients with advanced or metastatic UC ineligible for cisplatin-based first-line chemotherapy based on the results of a phase II trial but use of atezolizumab is restricted to PD-L1 positive patients. Recommendations Offer radical nephroureterectomy as a palliative treatment to symptomatic patients with resectable locally advanced tumours. First-line treatment for cisplatin-eligible patients Use cisplatin-containing combination chemotherapy with GC or HD-MVAC. Do not offer carboplatin or non-platinum combination chemotherapy. First-line treatment in patients unfit for cisplatin Offer checkpoint inhibitors pembrolizumab or atezolizumab depending on PD-L1 status. Offer carboplatin combination chemotherapy if PD-L1 is negative.

UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021

LE 3 2 3 4 1b 2a 2a 2a

2a

Strength rating Weak

Strong Strong Weak Strong

21

Second-line treatment Offer checkpoint inhibitor (pembrolizumab) to patients with disease progression during or after platinum-based combination chemotherapy for metastatic disease. Offer checkpoint inhibitor (atezolizumab or nivolumab) to patients with disease progression during or after platinum-based combination chemotherapy for metastatic disease. Only offer vinflunine to patients for metastatic disease as second-line treatment if immunotherapy or combination chemotherapy is not feasible. Alternatively, offer vinflunine as third- or subsequent-line treatment.

Strong Strong Strong

GC = gemcitabine plus cisplatin; HD-MVAC = high-dose intensity methotrexate, vinblastine, adriamycin plus cisplatin; PD-L1 = programmed death ligand 1; PCG = paclitaxel, cisplatin, gemcitabine.

8.

FOLLOW-UP

The risk of recurrence and death evolves during the follow-up period after surgery [270]. Stringent follow-up is mandatory to detect metachronous bladder tumours (probability increases over time [271]), local recurrence, and distant metastases. Section 8.1 presents the summary of evidence and recommendations for follow-up of UTUC. Surveillance regimens are based on cystoscopy and urinary cytology for > 5 years [12, 14, 15, 164]. Bladder recurrence is not considered a distant recurrence. When kidney-sparing surgery is performed, the ipsilateral UUT requires careful and long-term follow-up due to the high risk of disease recurrence [180, 272, 273] and progression to RNU beyond 5 years [274]. Despite endourological improvements, follow-up after kidney-sparing management is difficult and frequent, and repeated endoscopic procedures are necessary. Following kidney-sparing surgery, and as done in bladder cancer, an early repeated (second look) ureteroscopy within six to eight weeks after primary endoscopic treatment has been proposed, but is not yet routine practice [2, 181].

8.1

Summary of evidence and guidelines for the follow-up of UTUC

Summary of evidence Follow-up is more frequent and more stringent in patients who have undergone kidney-sparing treatment compared to radical nephroureterectomy.

Recommendations After radical nephroureterectomy Low-risk tumours Perform cystoscopy at three months. If negative, perform subsequent cystoscopy nine months later and then yearly, for five years. High-risk tumours Perform cystoscopy and urinary cytology at three months. If negative, repeat subsequent cystoscopy and cytology every three months for a period of two years, and every six months thereafter until five years, and then yearly. Perform computed tomography (CT) urography and chest CT every six months for two years, and then yearly. After kidney-sparing management Low-risk tumours Perform cystoscopy and CT urography at three and six months, and then yearly for five years. Perform ureteroscopy (URS) at three months. High-risk tumours Perform cystoscopy, urinary cytology, CT urography and chest CT at three and six months, and then yearly. Perform URS and urinary cytology in situ at three and six months.

22

LE 3

Strength rating

Weak

Weak

Weak

Weak Weak Weak Weak

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Adibi, M., et al. Oncological outcomes after radical nephroureterectomy for upper tract urothelial carcinoma: comparison over the three decades. Int J Urol, 2012. 19: 1060. https://pubmed.ncbi.nlm.nih.gov/22882743 Clements, M.B., et al. Robotic-Assisted Surgery for Upper Tract Urothelial Carcinoma: A Comparative Survival Analysis. Ann Surg Oncol, 2018. 25: 2550. https://pubmed.ncbi.nlm.nih.gov/29948423 Rodriguez, J.F., et al. Utilization and Outcomes of Nephroureterectomy for Upper Tract Urothelial Carcinoma by Surgical Approach. J Endourol, 2017. 31: 661. https://pubmed.ncbi.nlm.nih.gov/28537436 Aboumohamed, A.A., et al. Oncologic Outcomes Following Robot-Assisted Laparoscopic Nephroureterectomy with Bladder Cuff Excision for Upper Tract Urothelial Carcinoma. J Urol, 2015. 194: 1561. https://pubmed.ncbi.nlm.nih.gov/26192256 Xylinas, E., et al. Impact of Distal Ureter Management on Oncologic Outcomes Following Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma. European Urology, 2014. 65: 210. https://pubmed.ncbi.nlm.nih.gov/22579047 Xylinas, E., et al. Prediction of Intravesical Recurrence After Radical Nephroureterectomy: Development of a Clinical Decision-making Tool. European Urology, 2014. 65: 650. https://pubmed.ncbi.nlm.nih.gov/24070577 Phe, V., et al. Does the surgical technique for management of the distal ureter influence the outcome after nephroureterectomy? BJU Int, 2011. 108: 130. https://pubmed.ncbi.nlm.nih.gov/21070580 Kondo, T., et al. Template-based lymphadenectomy in urothelial carcinoma of the upper urinary tract: impact on patient survival. Int J Urol, 2010. 17: 848. https://pubmed.ncbi.nlm.nih.gov/20812922 Dominguez-Escrig, J.L., et al. Potential Benefit of Lymph Node Dissection During Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: A Systematic Review by the European Association of Urology Guidelines Panel on Non-muscle-invasive Bladder Cancer. Eur Urol Focus, 2019. 5: 224. https://pubmed.ncbi.nlm.nih.gov/29158169 Dong, F., et al. Lymph node dissection could bring survival benefits to patients diagnosed with clinically node-negative upper urinary tract urothelial cancer: a population-based, propensity scorematched study. Int J Clin Oncol, 2019. 24: 296. https://pubmed.ncbi.nlm.nih.gov/30334174 Lenis, A.T., et al. Role of surgical approach on lymph node dissection yield and survival in patients with upper tract urothelial carcinoma. Urol Oncol, 2018. 36: 9 e1. https://pubmed.ncbi.nlm.nih.gov/29066013 Moschini, M., et al. Trends of lymphadenectomy in upper tract urothelial carcinoma (UTUC) patients treated with radical nephroureterectomy. World J Urol, 2017. 35: 1541. https://pubmed.ncbi.nlm.nih.gov/28247066 Zareba, P., et al. Association between lymph node yield and survival among patients undergoing radical nephroureterectomy for urothelial carcinoma of the upper tract. Cancer, 2017. 123: 1741. https://pubmed.ncbi.nlm.nih.gov/28152158 Xylinas, E., et al. External validation of the pathological nodal staging score in upper tract urothelial carcinoma: A population-based study. Urol Oncol, 2017. 35: 33 e21. https://pubmed.ncbi.nlm.nih.gov/27816402 Xylinas, E., et al. Prediction of true nodal status in patients with pathological lymph node negative upper tract urothelial carcinoma at radical nephroureterectomy. J Urol, 2013. 189: 468. https://pubmed.ncbi.nlm.nih.gov/23253960 Matin, S.F., et al. Patterns of Lymphatic Metastases in Upper Tract Urothelial Carcinoma and Proposed Dissection Templates. J Urol, 2015. 194: 1567. https://pubmed.ncbi.nlm.nih.gov/26094807 Kondo, T., et al. Template-based lymphadenectomy in urothelial carcinoma of the renal pelvis: a prospective study. Int J Urol, 2014. 21: 453. https://pubmed.ncbi.nlm.nih.gov/24754341 Matin, S.F., et al. Incidence of downstaging and complete remission after neoadjuvant chemotherapy for high-risk upper tract transitional cell carcinoma. Cancer, 2010. 116: 3127. https://pubmed.ncbi.nlm.nih.gov/20564621

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Hwang, E.C., et al. Single-dose intravesical chemotherapy after nephroureterectomy for upper tract urothelial carcinoma. Cochrane Database Syst Rev, 2019. 5: Cd013160. https://pubmed.ncbi.nlm.nih.gov/31102534 Fang, D., et al. Prophylactic intravesical chemotherapy to prevent bladder tumors after nephroureterectomy for primary upper urinary tract urothelial carcinomas: a systematic review and meta-analysis. Urol Int, 2013. 91: 291. https://pubmed.ncbi.nlm.nih.gov/23948770 Harraz, A.M., et al. Single Versus Maintenance Intravesical Chemotherapy for the Prevention of Bladder Recurrence after Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: A Randomized Clinical Trial. Clin Genitourin Cancer, 2019. 17: e1108. https://pubmed.ncbi.nlm.nih.gov/31594736 Yamamoto, S., et al. Intravesical irrigation might prevent bladder recurrence in patients undergoing radical nephroureterectomy for upper urinary tract urothelial carcinoma. Int J Urol, 2019. 26: 791. https://pubmed.ncbi.nlm.nih.gov/31081198 Dong, F., et al. How do organ-specific metastases affect prognosis and surgical treatment for patients with metastatic upper tract urothelial carcinoma: first evidence from population based data. Clin Exp Metastasis, 2017. 34: 467. https://pubmed.ncbi.nlm.nih.gov/29500709 Seisen, T., et al. Efficacy of Systemic Chemotherapy Plus Radical Nephroureterectomy for Metastatic Upper Tract Urothelial Carcinoma. European Urology, 2017. 71: 714. https://pubmed.ncbi.nlm.nih.gov/27912971 Moschini, M., et al. Efficacy of Surgery in the Primary Tumor Site for Metastatic Urothelial Cancer: Analysis of an International, Multicenter, Multidisciplinary Database. Eur Urol Oncol, 2020. 3: 94. https://pubmed.ncbi.nlm.nih.gov/31307962 Nazzani, S., et al. Survival Effect of Nephroureterectomy in Metastatic Upper Urinary Tract Urothelial Carcinoma. Clin Genitourin Cancer, 2019. 17: e602. https://pubmed.ncbi.nlm.nih.gov/31005472 Siefker-Radtke, A.O., et al. Is there a role for surgery in the management of metastatic urothelial cancer? The M. D. Anderson experience. J Urol, 2004. 171: 145. https://pubmed.ncbi.nlm.nih.gov/14665863 Abe, T., et al. Impact of multimodal treatment on survival in patients with metastatic urothelial cancer. Eur Urol, 2007. 52: 1106. https://pubmed.ncbi.nlm.nih.gov/17367917 Lehmann, J., et al. Surgery for metastatic urothelial carcinoma with curative intent: the German experience (AUO AB 30/05). Eur Urol, 2009. 55: 1293. https://pubmed.ncbi.nlm.nih.gov/19058907 Faltas, B.M., et al. Metastasectomy in older adults with urothelial carcinoma: Population-based analysis of use and outcomes. Urol Oncol, 2018. 36: 9 e11. https://pubmed.ncbi.nlm.nih.gov/28988653 Moschini, M., et al. Impact of Primary Tumor Location on Survival from the European Organization for the Research and Treatment of Cancer Advanced Urothelial Cancer Studies. J Urol, 2018. 199: 1149. https://pubmed.ncbi.nlm.nih.gov/29158104 Powles, T., et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med, 2020. 383: 1218. https://pubmed.ncbi.nlm.nih.gov/32945632 Balar, A.V., et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet, 2017. 389: 67. https://pubmed.ncbi.nlm.nih.gov/27939400 Balar, A.V., et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol, 2017. 18: 1483. https://pubmed.ncbi.nlm.nih.gov/28967485 Alva, A., et al. LBA23 Pembrolizumab (P) combined with chemotherapy (C) vs C alone as first-line (1L) therapy for advanced urothelial carcinoma (UC): KEYNOTE-361. Ann Oncol 2020. 31: S1142. https://www.annalsofoncology.org/article/S0923-7534(20)42334-8/abstract Powles, T., et al. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol, 2020. 21: 1574. https://pubmed.ncbi.nlm.nih.gov/32971005

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Study of Nivolumab in Combination With Ipilimumab or Standard of Care Chemotherapy Compared to the Standard of Care Chemotherapy Alone in Treatment of Patients With Untreated Inoperable or Metastatic Urothelial Cancer (CheckMate901). 2019 [access date March 2021]. https://clinicaltrials.gov/ct2/show/NCT03036098 A Phase 1/2 Study Exploring the Safety, Tolerability, and Efficacy of Pembrolizumab (MK-3475) in Combination With Epacadostat (INCB024360) in Subjects With Selected Cancers (INCB 24360-202 / MK-3475-037 / KEYNOTE-037/ ECHO-202). 2019 [access date March 2021]. https://clinicaltrials.gov/ct2/show/NCT02178722 Study of Durvalumab Given With Chemotherapy, Durvalumab in Combination With Tremelimumab Given With Chemotherapy, or Chemotherapy in Patients With Unresectable Urothelial Cancer (NILE). 2020. p. NCT03682068 [access date March 2021]. https://www.clinicaltrials.gov/ct2/show/NCT03682068 Heers, H., et al. Vinflunine in the Treatment of Upper Tract Urothelial Carcinoma - Subgroup Analysis of an Observational Study. Anticancer Res, 2017. 37: 6437. https://pubmed.ncbi.nlm.nih.gov/29061830 Bellmunt, J., et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med, 2017. 376: 1015. https://pubmed.ncbi.nlm.nih.gov/28212060 Rosenberg, J.E., et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a singlearm, multicentre, phase 2 trial. Lancet, 2016. 387: 1909. https://pubmed.ncbi.nlm.nih.gov/26952546 Powles, T., et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet, 2018. 391: 748. https://pubmed.ncbi.nlm.nih.gov/29268948 Sharma, P., et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol, 2017. 18: 312. https://pubmed.ncbi.nlm.nih.gov/28131785 Patel, M.R., et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol, 2018. 19: 51. https://pubmed.ncbi.nlm.nih.gov/29217288 Apolo, A.B., et al. Avelumab, an Anti-Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study. J Clin Oncol, 2017. 35: 2117. https://pubmed.ncbi.nlm.nih.gov/28375787 Powles, T., et al. Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma: Updated Results From a Phase 1/2 Open-label Study. JAMA Oncol, 2017. 3: e172411. https://pubmed.ncbi.nlm.nih.gov/28817753 Sharma, P., et al. Nivolumab Alone and With Ipilimumab in Previously Treated Metastatic Urothelial Carcinoma: CheckMate 032 Nivolumab 1 mg/kg Plus Ipilimumab 3 mg/kg Expansion Cohort Results. J Clin Oncol, 2019. 37: 1608. https://pubmed.ncbi.nlm.nih.gov/31100038 Siefker-Radtke, A., et al. Immunotherapy in metastatic urothelial carcinoma: focus on immune checkpoint inhibition. Nat Rev Urol, 2018. 15: 112. https://pubmed.ncbi.nlm.nih.gov/29205200 Loriot, Y., et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. New England Journal of Medicine, 2019. 381: 338. https://pubmed.ncbi.nlm.nih.gov/31340094 Ploussard, G., et al. Conditional survival after radical nephroureterectomy for upper tract carcinoma. Eur Urol, 2015. 67: 803. https://pubmed.ncbi.nlm.nih.gov/25145551 Shigeta, K., et al. The Conditional Survival with Time of Intravesical Recurrence of Upper Tract Urothelial Carcinoma. J Urol, 2017. 198: 1278. https://pubmed.ncbi.nlm.nih.gov/28634017 Mandalapu, R.S., et al. Update of the ICUD-SIU consultation on upper tract urothelial carcinoma 2016: treatment of low-risk upper tract urothelial carcinoma. World J Urol, 2017. 35: 355. https://pubmed.ncbi.nlm.nih.gov/27233780

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10. CONFLICT OF INTEREST All members of the Non-Muscle-Invasive Bladder Cancer Guidelines working panel have provided disclosure statements on all relationships that they have that might be perceived to be a potential source of a conflict of interest. This information is publically accessible through the European Association of Urology website: http://uroweb.org/guideline/upper-urinary-tract-urothelial-cell-carcinoma/. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation, and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

11. CITATION INFORMATION The format in which to cite the EAU Guidelines will vary depending on the style guide of the journal in which the citation appears. Accordingly, the number of authors or whether, for instance, to include the publisher, location, or an ISBN number may vary. The compilation of the complete Guidelines should be referenced as: EAU Guidelines. Edn. presented at the EAU Annual Congress Milan, 2021. ISBN 978-94-92671-13-4. If a publisher and/or location is required, include: EAU Guidelines Office, Arnhem, The Netherlands. http://uroweb.org/guidelines/compilations-of-all-guidelines/ References to individual guidelines should be structured in the following way: Contributors’ names. Title of resource. Publication type. ISBN. Publisher and publisher location, year.

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EAU - EANM - ESTRO ESUR - ISUP - SIOG Guidelines on

Prostate Cancer N. Mottet (Chair), P. Cornford (Vice-chair), R.C.N. van den Bergh, E. Briers, Expert Patient Advocate (European Prostate Cancer Coalition/Europa UOMO), M. De Santis, S. Gillessen, J. Grummet, A.M. Henry, T.H. van der Kwast, T.B. Lam, M.D. Mason, S. O’Hanlon, D.E. Oprea-Lager, G. Ploussard, H.G. van der Poel, O. Rouvière, I.G. Schoots. D. Tilki, T. Wiegel Guidelines Associates: T. Van den Broeck, M. Cumberbatch, A. Farolfi, N. Fossati, G. Gandaglia, N. Grivas, M. Lardas, M. Liew, L. Moris, P-P.M. Willemse

© European Association of Urology 2021

TABLE OF CONTENTS

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1. INTRODUCTION 1.1 Aims and scope 1.2 Panel composition 1.2.1 Acknowledgement 1.3 Available publications 1.4 Publication history and summary of changes 1.4.1 Publication history 1.4.2 Summary of changes

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METHODS 2.1 Data identification 2.2 Review 2.3 Future goals

3. EPIDEMIOLOGY AND AETIOLOGY 3.1 Epidemiology 3.2 Aetiology 3.2.1 Family history / hereditary prostate cancer 3.2.1.1 Germline mutations and prostate cancer 3.2.2 Risk factors 3.2.2.1 Metabolic syndrome 3.2.2.1.1 Diabetes/metformin 3.2.2.1.2 Cholesterol/statins 3.2.2.1.3 Obesity 3.2.2.2 Dietary factors 3.2.2.3 Hormonally active medication 3.2.2.3.1 5-alpha-reductase inhibitors (5-ARIs) 3.2.2.3.2 Testosterone 3.2.2.4 Other potential risk factors 3.2.3 Summary of evidence for epidemiology and aetiology

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CLASSIFICATION AND STAGING SYSTEMS 4.1 Classification 4.2 Gleason score and International Society of Urological Pathology 2014 grade 4.3 Prognostic relevance of stratification 4.4 Guidelines for classification and staging systems

5. DIAGNOSTIC EVALUATION 5.1 Screening and early detection 5.1.1 Screening 5.1.2 Early detection 5.1.3 Genetic testing for inherited prostate cancer 5.1.4 Guidelines for germline testing* 5.1.5 Guidelines for screening and early detection 5.2 Clinical diagnosis 5.2.1 Digital rectal examination 5.2.2 Prostate-specific antigen 5.2.2.1 PSA density 5.2.2.2 PSA velocity and doubling time 5.2.2.3 Free/total PSA ratio 5.2.3 Biomarkers in prostate cancer 5.2.3.1 Blood based biomarkers: PHI/4K score/IsoPSA 5.2.3.2 Urine biomarkers: PCA3/SelectMDX/Mi Prostate score (MiPS)/ExoDX 5.2.3.3 Tests to select men for a repeat biopsy 5.2.3.4 Guidelines for risk-assessment of asymptomatic men 5.2.4 The role of imaging in clinical diagnosis 5.2.4.1 Transrectal ultrasound and ultrasound-based techniques 5.2.4.2 Multiparametric magnetic resonance imaging

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5.2.4.2.1 Multiparametric magnetic resonance imaging performance in detecting PCa 28 5.2.4.2.2 Targeted biopsy improves the detection of ISUP grade > 2 cancer as compared to systematic biopsy. 28 5.2.4.2.3 MRI-TBx without systematic biopsy reduces the detection of ISUP grade 1 PCa as compared to systematic biopsy. 29 5.2.4.2.4 The added value of systematic and targeted biopsy 29 5.2.4.2.5 Number of biopsy procedures potentially avoided in the ‘MR pathway’ 30 5.2.4.2.6 Other considerations 30 5.2.4.2.6.1 Multiparametric magnetic resonance imaging reproducibility 30 5.2.4.2.6.2 Targeted biopsy accuracy and reproducibility 31 5.2.4.2.6.3 Role of risk-stratification 31 5.2.4.2.6.4 Pre-biopsy MRI and MRI-TBx may induce an ISUP prostate cancer grade shift, as a result of improved diagnosis 33 5.2.4.2.7 Summary of evidence and practical considerations on pre-biopsy MRI and MRI-TBx 33 5.2.4.3 Guidelines for imaging in PCa detection 33 5.2.5 Baseline biopsy 34 5.2.6 Repeat biopsy 34 5.2.6.1 Repeat biopsy after previously negative biopsy 34 5.2.6.2 Saturation biopsy 34 5.2.7 Prostate biopsy procedure 34 5.2.7.1 Sampling sites and number of cores 34 5.2.7.2 Antibiotics prior to biopsy 35 5.2.7.2.1 Transperineal prostate biopsy 35 5.2.7.2.2 Transrectal prostate biopsy 35 5.2.7.3 Summary of evidence and recommendations for performing prostate biopsy (in line with the Urological Infections Guidelines Panel) 36 5.2.7.4 Local anaesthesia prior to biopsy 37 5.2.7.5 Complications 38 5.2.7.6 Seminal vesicle biopsy 38 5.2.7.7 Transition zone biopsy 38 5.2.8 Pathology of prostate needle biopsies 38 5.2.8.1 Processing 38 5.2.8.2 Microscopy and reporting 38 5.2.8.2.1 Recommended terminology for reporting prostate biopsies 39 5.2.8.3 Tissue-based prognostic biomarker testing 39 5.2.8.4 Histopathology of radical prostatectomy specimens 40 5.2.8.4.1 Processing of radical prostatectomy specimens 40 5.2.8.4.1.1 Guidelines for processing prostatectomy specimens 40 5.2.8.4.2 Radical prostatectomy specimen report 40 5.2.8.4.3 ISUP grade in prostatectomy specimens 41 5.2.8.4.4 Definition of extraprostatic extension 41 5.2.8.4.5 PCa volume 42 5.2.8.4.6 Surgical margin status 42 5.3 Diagnosis - Clinical Staging 42 5.3.1 T-staging 42 5.3.1.1 TRUS 42 5.3.1.2 MRI 42 5.3.2 N-staging 43 5.3.2.1 Computed tomography and magnetic resonance imaging 43 5.3.2.2 Risk calculators incorporating MRI findings 43 5.3.2.3 Choline PET/CT 43 5.3.2.4 Prostate-specific membrane antigen-based PET/CT 43 5.3.3 M-staging 44

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5.3.3.1 Bone scan 5.3.3.2 Fluoride PET and PET/CT, choline PET/CT and MRI 5.3.3.3 Prostate-specific membrane antigen-based PET/CT 5.3.4 Summary of evidence and practical considerations on initial N/M staging 5.3.5 Summary of evidence and guidelines for staging of prostate cancer 5.4 Estimating life expectancy and health status 5.4.1 Introduction 5.4.2 Life expectancy 5.4.3 Health status screening 5.4.3.1 Co-morbidity 5.4.3.2 Nutritional status 5.4.3.3 Cognitive function 5.4.3.4 Physical function 5.4.3.5 Shared decision-making 5.4.4 Conclusion 5.4.5 Guidelines for evaluating health status and life expectancy

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6. TREATMENT 6.1 Treatment modalities 6.1.1 Deferred treatment (active surveillance/watchful waiting) 6.1.1.1 Definitions 6.1.1.2 Active surveillance 6.1.1.3 Watchful Waiting 6.1.1.3.1 Outcome of watchful waiting compared with active treatment 6.1.1.4 The ProtecT study 6.1.2 Radical prostatectomy 6.1.2.1 Introduction 6.1.2.2 Pre-operative preparation 6.1.2.2.1 Pre-operative patient education 6.1.2.3 Surgical techniques 6.1.2.3.1 Robotic anterior versus Retzius-sparing dissection 6.1.2.3.2 Pelvic lymph node dissection 6.1.2.3.3 Sentinel node biopsy analysis 6.1.2.3.4 Prostatic anterior fat pad dissection and histologic analysis 6.1.2.3.5 Management of the dorsal venous complex 6.1.2.3.6 Nerve-sparing surgery 6.1.2.3.7 Lymph-node-positive patients during radical prostatectomy 6.1.2.3.8 Removal of seminal vesicles 6.1.2.3.9 Techniques of vesico-urethral anastomosis 6.1.2.3.10 Bladder neck management 6.1.2.3.11 Urethral length preservation 6.1.2.3.12 Cystography prior to catheter removal 6.1.2.3.13 Urinary catheter 6.1.2.3.14 Use of a pelvic drain 6.1.2.4 Acute and chronic complications of surgery 6.1.2.4.1 Effect of anterior and posterior reconstruction on continence 6.1.2.4.2 Deep venous thrombosis prophylaxis 6.1.2.4.3 Early complications of extended lymph node dissection 6.1.3 Radiotherapy 6.1.3.1 External beam radiation therapy 6.1.3.1.1 Technical aspects: intensity-modulated external-beam radiotherapy and volumetric arc external-beam radiotherapy 6.1.3.1.2 Dose escalation 6.1.3.1.3 Hypofractionation 6.1.3.1.4 Neoadjuvant or adjuvant hormone therapy plus radiotherapy

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6.1.3.1.5 Combined dose-escalated radiotherapy and androgen deprivation therapy 64 6.1.3.2 Proton beam therapy 65 6.1.3.3 Spacer during external beam radiation therapy 65 6.1.3.4 Brachytherapy 65 6.1.3.4.1 Low-dose rate (LDR) brachytherapy 65 6.1.3.4.2 High-dose rate brachytherapy 66 6.1.3.5 Acute side effects of external beam radiotherapy and brachytherapy 66 6.1.4 Hormonal therapy 67 6.1.4.1 Introduction 67 6.1.4.1.1 Different types of hormonal therapy 67 6.1.4.1.1.1 Testosterone-lowering therapy (castration) 67 6.1.4.1.1.1.1 Castration level 67 6.1.4.1.1.1.2 Bilateral orchiectomy 67 6.1.4.1.1.1.3 Oestrogens 67 6.1.4.1.1.1.4 Luteinising-hormone-releasing hormone agonists 67 6.1.4.1.1.1.5 Luteinising-hormone-releasing hormone antagonists 67 6.1.4.1.1.1.6 Anti-androgens 68 6.1.4.1.1.1.6.1 Steroidal anti-androgens 68 6.1.4.1.1.1.6.2 Non-steroidal anti-androgens 68 6.1.4.1.1.2 New androgen receptor pathway targetting agents (ARTA) 68 6.1.4.1.1.2.1 Abiraterone acetate 68 6.1.4.1.1.2.2 Apalutamide, darolutamide, enzalutamide (alphabetical order) 68 6.1.4.1.1.3 New compounds 69 6.1.4.1.1.3.1 PARP inhibitors 69 6.1.4.1.1.3.2 Immune checkpoint inhibitors 69 6.1.4.1.1.3.3 Protein kinase B (AKT) inhibitors 69 6.1.5 Investigational therapies 69 6.1.5.1 Background 69 6.1.5.2 Cryotherapy 69 6.1.5.3 High-intensity focused ultrasound 70 6.1.5.4 Focal therapy 70 6.1.6 General guidelines for the treatment of prostate cancer 71 6.2 Treatment by disease stages 72 6.2.1 Treatment of low-risk disease 72 6.2.1.1 Active surveillance 72 6.2.1.1.1 Active surveillance - inclusion criteria 72 6.2.1.1.2 Tissue-based prognostic biomarker testing 72 6.2.1.1.3 Imaging for treatment selection 72 6.2.1.1.4 Monitoring during active surveillance 73 6.2.1.1.5 Active Surveillance - when to change strategy 74 6.2.1.2 Alternatives to active surveillance for the treatment of low-risk disease 74 6.2.1.3 Summary of evidence and guidelines for the treatment of low-risk disease 74 6.2.2 Treatment of intermediate-risk disease 75 6.2.2.1 Active Surveillance 75 6.2.2.2 Surgery 75 6.2.2.3 Radiation therapy 75 6.2.2.3.1 Recommended IMRT for intermediate-risk PCa 75 6.2.2.3.2 Brachytherapy monotherapy 75 6.2.2.4 Other options for the primary treatment of intermediate-risk PCa (experimental therapies) 75 6.2.2.5 Guidelines for the treatment of intermediate-risk disease 76 6.2.3 Treatment of high-risk localised disease 76 6.2.3.1 Radical prostatectomy 76 6.2.3.1.1 ISUP grade 4–5 76 6.2.3.1.2 Prostate-specific antigen > 20 ng/mL 77 PROSTATE CANCER - LIMITED UPDATE 2021

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6.2.3.1.3 Radical prostatectomy in cN0 patients who are found to have pathologically confirmed lymph node invasion (pN1) 77 6.2.3.2 External beam radiation therapy 77 6.2.3.2.1 Recommended external beam radiation therapy treatment policy for high-risk localised PCa 77 6.2.3.2.2 Lymph node irradiation in cN0 77 6.2.3.2.3 Brachytherapy boost 77 6.2.3.3 Options other than surgery and radiotherapy for the primary treatment of localised PCa 77 6.2.3.4 Guidelines for radical treatment of high-risk localised disease 78 6.2.4 Treatment of locally advanced PCa 78 6.2.4.1 Surgery 78 6.2.4.2 Radiotherapy for locally advanced PCa 78 6.2.4.3 Treatment of cN1 M0 PCa 78 6.2.4.3.1 Guidelines for the management of cN1 M0 prostate cancer 80 6.2.4.4 Options other than surgery and radiotherapy for primary treatment 80 6.2.4.4.1 Investigational therapies 80 6.2.4.4.2 Androgen deprivation therapy monotherapy 80 6.2.4.5 Guidelines for radical treatment of locally-advanced disease 80 6.2.5 Adjuvant treatment after radical prostatectomy 80 6.2.5.1 Introduction 80 6.2.5.2 Risk factors for relapse 81 6.2.5.2.1 Biomarker-based risk stratification after radical prostatectomy 81 6.2.5.3 Immediate (adjuvant) post-operative external irradiation after RP (cN0 or pN0) 81 6.2.5.4 Comparison of adjuvant- and salvage radiotherapy 82 6.2.5.5 Adjuvant androgen ablation in men with N0 disease 83 6.2.5.6 Adjuvant treatment in pN1 disease 83 6.2.5.6.1 Adjuvant androgen ablation alone 83 6.2.5.6.2 Adjuvant radiotherapy combined with ADT in pN1 disease 83 6.2.5.6.3 Observation of pN1 patients after radical prostatectomy and extended lymph node dissection 84 6.2.5.7 Guidelines for adjuvant treatment in pN0 and pN1 disease after radical prostatectomy 84 6.2.5.8 Guidelines for non-curative or palliative treatments in prostate cancer 84 6.2.6 Persistent PSA after radical prostatectomy 85 6.2.6.1 Natural history of persistently elevated PSA after RP 85 6.2.6.2 Imaging in patients with persistently elevated PSA after RP 86 6.2.6.3 Impact of post-operative RT and/or ADT in patients with persistent PSA 87 6.2.6.4 Conclusion 87 6.2.6.5 Recommendations for the management of persistent PSA after radical prostatectomy 88 6.3 Management of PSA-only recurrence after treatment with curative intent 88 6.3.1 Background 88 6.3.2 Definitions of clinically relevant PSA relapse 88 6.3.3 Natural history of biochemical recurrence 88 6.3.4 The role of imaging in PSA-only recurrence 89 6.3.4.1 Assessment of metastases 89 6.3.4.1.1 Bone scan and abdominopelvic CT 89 6.3.4.1.2 Choline PET/CT 89 6.3.4.1.3 Fluoride PET and PET/CT 89 6.3.4.1.4 Fluciclovine PET/CT 89 6.3.4.1.5 Prostate-specific membrane antigen based PET/CT 90 6.3.4.1.6 Whole-body and axial MRI 90 6.3.4.2 Assessment of local recurrences 90 6.3.4.2.1 Local recurrence after radical prostatectomy 90 6.3.4.2.2 Local recurrence after radiation therapy 91 6.3.4.3 Summary of evidence on imaging in case of biochemical recurrence 91

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6.3.4.4 Guidelines for imaging in patients with biochemical recurrence 91 6.3.5 Treatment of PSA-only recurrences 91 6.3.5.1 Treatment of PSA-only recurrences after radical prostatectomy 91 6.3.5.1.1 Salvage radiotherapy for PSA-only recurrence after radical prostatectomy (cTxcN0M0, without PET/ CT) 91 6.3.5.1.2 Salvage radiotherapy combined with androgen deprivation therapy (cTxcN0, without PET/CT) 93 6.3.5.1.2.1 Target volume, dose, toxicity 94 6.3.5.1.2.2 Salvage RT with or without ADT (cTx CN0/1) (with PET/CT) 95 6.3.5.1.2.3 Metastasis-directed therapy for rcN+ (with PET/CT) 95 6.3.5.1.3 Salvage lymph node dissection 95 6.3.5.1.4 Comparison of adjuvant- and salvage radiotherapy 96 6.3.5.2 Management of PSA failures after radiation therapy 96 6.3.5.2.1 Salvage radical prostatectomy 96 6.3.5.2.1.1 Oncological outcomes 96 6.3.5.2.1.2 Morbidity 97 6.3.5.2.1.3 Summary of salvage radical prostatectomy 97 6.3.5.2.2 Salvage cryoablation of the prostate 97 6.3.5.2.2.1 Oncological outcomes 97 6.3.5.2.2.2 Morbidity 98 6.3.5.2.2.3 Summary of salvage cryoablation of the prostate 98 6.3.5.2.3 Salvage re-irradiation 98 6.3.5.2.3.1 Salvage brachytherapy for radiotherapy failure 98 6.3.5.2.3.2 Salvage stereotactic ablative body radiotherapy for radiotherapy failure 99 6.3.5.2.3.2.1 Oncological outcomes and morbidity 99 6.3.5.2.3.2.2 Morbidity 99 6.3.5.2.3.2.3 Summary of salvage stereotactic ablative body radiotherapy 99 6.3.5.2.4 Salvage high-intensity focused ultrasound 99 6.3.5.2.4.1 Oncological outcomes 99 6.3.5.2.4.2 Morbidity 100 6.3.5.2.4.3 Summary of salvage high-intensity focused ultrasound 100 6.3.6 Hormonal therapy for relapsing patients 100 6.3.7 Observation 101 6.3.8 Guidelines for second-line therapy after treatment with curative intent 101 6.4 Treatment: Metastatic prostate cancer 101 6.4.1 Introduction 101 6.4.2 Prognostic factors 101 6.4.3 First-line hormonal treatment 102 6.4.3.1 Non-steroidal anti-androgen monotherapy 102 6.4.3.2 Intermittent versus continuous androgen deprivation therapy 102 6.4.3.3 Immediate versus deferred androgen deprivation therapy 103 6.4.4 Combination therapies 103 6.4.4.1 ‘Complete’ androgen blockade 103 6.4.4.2 Androgen deprivation combined with other agents 103 6.4.4.2.1 Androgen deprivation therapy combined with chemotherapy 103 6.4.4.2.2 Combination with the new hormonal treatments (abiraterone, apalutamide, enzalutamide) 104 6.4.5 Treatment selection and patient selection 106 6.4.6 Deferred treatment for metastatic PCa (stage M1) 106 6.4.7 Treatment of the primary tumour in newly diagnosed metastatic disease 106 6.4.8 Metastasis-directed therapy in M1-patients 107 6.4.9 Guidelines for the first-line treatment of metastatic disease 107

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6.5 Treatment: Castration-resistant PCa (CRPC) 6.5.1 Definition of CRPC 6.5.2 Management of mCRPC - general aspects 6.5.2.1 Molecular diagnostics 6.5.3 Treatment decisions and sequence of available options 6.5.4 Non-metastatic CRPC 6.5.5 Metastatic CRPC 6.5.5.1 Conventional androgen deprivation in CRPC 6.5.6 First-line treatment of metastatic CRPC 6.5.6.1 Abiraterone 6.5.6.2 Enzalutamide 6.5.6.3 Docetaxel 6.5.6.4 Sipuleucel-T 6.5.6.5 Ipatasertib 6.5.7 Second-line treatment for mCRPC and sequence 6.5.7.1 Cabazitaxel 6.5.7.2 Abiraterone acetate after prior docetaxel 6.5.7.3 Enzalutamide after docetaxel 6.5.7.4 Radium-223 6.5.8 Treatment after docetaxel and one line of hormonal treatment for mCRPC 6.5.8.1 PARP inhibitors for mCRPC 6.5.8.2 Sequencing treatment 6.5.8.2.1 ARTA -> ARTA (chemotherapy-naïve patients) 6.5.8.2.2 ARTA -> PARP inhibitor/olaparib 6.5.8.2.3 Docetaxel for mHSPC -> docetaxel rechallenge 6.5.8.2.4 ARTA -> docetaxel or docetaxel -> ARTA followed by PARP inhibitor 6.5.8.2.5 ARTA before or after docetaxel 6.5.8.2.6 ARTA –> docetaxel -> cabazitaxel or docetaxel –> ARTA -> cabazitaxel 6.5.9 Prostate-specific membrane antigen (PSMA) therapy 6.5.9.1 Background 6.5.9.2 PSMA-based therapy 6.5.10 Immunotherapy for mCRPC 6.5.11 Monitoring of treatment 6.5.12 When to change treatment 6.5.13 Symptomatic management in metastatic CRPC 6.5.13.1 Common complications due to bone metastases 6.5.13.2 Preventing skeletal-related events 6.5.13.2.1 Bisphosphonates 6.5.13.2.2 RANK ligand inhibitors 6.5.14 Summary of evidence and guidelines for life-prolonging treatments of castrate-resistant disease 6.5.15 Guidelines for systematic treatments of castrate-resistant disease 6.5.16 Guidelines for supportive care of castrate-resistant disease 6.5.17 Guideline for non-metastatic castrate-resistant disease 6.6 Summary of guidelines for the treatment of prostate cancer 6.6.1 General guidelines recommendations for treatment of prostate cancer 6.6.2 Guidelines recommendations for the various disease stages 6.6.3 Guidelines for metastatic disease, second-line and palliative treatments 7. FOLLOW-UP 7.1 Follow-up: After local treatment 7.1.1 Definition 7.1.2 Why follow-up? 7.1.3 How to follow-up? 7.1.3.1 Prostate-specific antigen monitoring 7.1.3.1.1 Active surveillance follow-up 7.1.3.1.2 Prostate-specific antigen monitoring after radical prostatectomy

8

108 108 108 108 108 108 109 109 110 110 110 111 111 111 112 112 113 113 113 113 114 114 114 115 115 115 115 115 115 115 115 115 115 116 116 116 116 116 117 117 118 118 118 118 119 119 122 124 124 124 124 124 124 124 124

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7.1.3.1.3 Prostate-specific antigen monitoring after radiotherapy 124 7.1.3.1.4 Digital rectal examination 125 7.1.3.1.5 Transrectal ultrasound, bone scintigraphy, CT, MRI and PET/CT 125 7.1.4 How long to follow-up? 125 7.1.5 Summary of evidence and guidelines for follow-up after treatment with curative intent 125 7.2 Follow-up: During first line hormonal treatment (androgen sensitive period) 125 7.2.1 Introduction 125 7.2.2 Purpose of follow-up 125 7.2.3 General follow-up of men on ADT 126 7.2.3.1 Testosterone monitoring 126 7.2.3.2 Liver function monitoring 126 7.2.3.3 Serum creatinine and haemoglobine 126 7.2.3.4 Monitoring of metabolic complications 126 7.2.3.5 Monitoring bone problems 126 7.2.3.6 Monitoring lifestyle and cognition 127 7.2.4 Methods of follow-up in men on ADT without metastases 127 7.2.4.1 Prostate-specific antigen monitoring 127 7.2.4.2 Imaging 127 7.2.5 Methods of follow-up in men under ADT for metastatic hormone-sensitive PCa 127 7.2.5.1 PSA monitoring 127 7.2.5.2 Imaging as a marker of response in metastatic PCa 127 7.2.6 Guidelines for follow-up during hormonal treatment 128 8. QUALITY OF LIFE OUTCOMES IN PROSTATE CANCER 8.1 Introduction 8.2 Adverse effects of PCa therapies 8.2.1 Surgery 8.2.2 Radiotherapy 8.2.2.1 Side-effects of external beam radiotherapy 8.2.2.2 Side effects from brachytherapy 8.2.3 Local primary whole-gland treatments other than surgery or radiotherapy 8.2.3.1 Cryosurgery 8.2.3.2 High-intensity focused ultrasound 8.2.4 Hormonal therapy 8.2.4.1 Sexual function 8.2.4.2 Hot flushes 8.2.4.3 Non-metastatic bone fractures 8.2.4.4 Metabolic effects 8.2.4.5 Cardiovascular morbidity 8.2.4.6 Fatigue 8.2.4.7 Neurological side effects 8.3 Overall quality of life in men with PCa 8.3.1 Long-term (> 12 months) quality of life outcomes in men with localised disease 8.3.1.1 Men undergoing local treatments 8.3.1.2 Guidelines for quality of life in men undergoing local treatments 8.3.2 Improving quality of life in men who have been diagnosed with PCa 8.3.2.1 Men undergoing local treatments 8.3.2.2 Men undergoing systemic treatments 8.3.2.3 Decision regret 8.3.2.4 Decision aids in prostate cancer 8.3.2.5 Guidelines for quality of life in men undergoing systemic treatments

128 128 128 128 129 129 129 129 129 129 129 130 130 130 130 131 131 131 131 132 132 133 133 133 133 134 134 135

9.

REFERENCES

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CONFLICT OF INTEREST

211

11.

CITATION INFORMATION

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1.

INTRODUCTION

1.1

Aims and scope

The Prostate Cancer (PCa) Guidelines Panel have prepared this guidelines document to assist medical professionals in the evidence-based management of PCa. It must be emphasised that clinical guidelines present the best evidence available to the experts but following guideline recommendations will not necessarily result in the best outcome. Guidelines can never replace clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions - also taking personal values and preferences/individual circumstances of patients into account. Guidelines are not mandates and do not purport to be a legal standard of care.

1.2

Panel composition

The PCa Guidelines Panel consists of an international multidisciplinary group of urologists, radiation oncologists, medical oncologists, radiologists, a pathologist, a geriatrician and a patient representative. All imaging sections in the text have been developed jointly with the European Society of Urogenital Radiology (ESUR) and the European Association of Nuclear Medicine (EANM). Representatives of the ESUR and the EANM in the PCa Guidelines Panel are (in alphabetical order): Dr. D. Oprea-Lager, Prof.Dr. O Rouvière and Dr. I.G. Schoots. All radiotherapy sections have been developed jointly with the European Society for Radiotherapy & Oncology (ESTRO). Representatives of ESTRO in the PCa Guidelines Panel are (in alphabetical order): Prof.Dr. A.M. Henry, Prof.Dr. M.D. Mason and Prof.Dr. T. Wiegel. The International Society of Urological Pathology is represented by Prof.Dr. T. van der Kwast. Dr. S. O’Hanlon, consultant geriatrician, representing the International Society of Geriatric Oncology (SOIG) contributed to the sections addressing life expectancy, health status and quality of life in particular. Dr. E. Briers, expert Patient Advocate Hasselt-Belgium representing the patient voice as delegated by the European Prostate Cancer Coalition/Europa UOMO. All experts involved in the production of this document have submitted potential conflict of interest statements which can be viewed on the EAU website Uroweb: https://uroweb.org/guideline/prostate-cancer/. 1.2.1 Acknowledgement The PCa Guidelines Panel gratefully acknowledges the assistance and general guidance provided by Prof.Dr. M. Bolla, honorary member of the PCa Guidelines Panel.

1.3

Available publications

A quick reference document (Pocket guidelines) is available, both in print and as an app for iOS and Android devices. These are abridged versions which may require consultation together with the full text version. Several scientific publications are available [1, 2] as are a number of translations of all versions of the PCa Guidelines. All documents can be accessed on the EAU website: http://uroweb.org/guideline/prostate-cancer/.

1.4

Publication history and summary of changes

1.4.1 Publication history The EAU PCa Guidelines were first published in 2001. This 2021 document presents an update of the 2020 PCa Guidelines publication. 1.4.2 Summary of changes The literature for the complete document has been assessed and updated based upon a review of all recommendations and creation of appropriate GRADE forms. Evidence summaries and recommendations have been amended throughout the current document and several new sections have been added. All chapters of the 2021 PCa Guidelines have been updated. New data have been included in the following sections, resulting in new sections and added and revised recommendations in:

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5.1.4 Guidelines for germline testing* Recommendations Consider germline testing in men with metastatic PCa. Consider germline testing in men with high-risk PCa who have a family member diagnosed with PCa at age < 60 years. Consider germline testing in men with multiple family members diagnosed with PCa at age < 60 years or a family member who died from PCa. Consider germline testing in men with a family history of high-risk germline mutations or a family history of multiple cancers on the same side of the family.

Strength rating weak weak weak weak

*Genetic counseling is required prior to germline testing.

5.2.7.3 Summary of evidence and recommendations for performing prostate biopsy (in line with the Urological Infections Guidelines Panel) Summary of evidence A meta-analysis of seven studies including 1,330 patients showed significantly reduced infectious complications in patients undergoing transperineal biopsy as compared to transrectal biopsy. Meta-analysis of eight RCTs including 1,786 men showed that use of a rectal povidone-iodine preparation before transrectal biopsy, in addition to antimicrobial prophylaxis, resulted in a significantly lower rate of infectious complications. A meta-analysis on eleven studies with 1,753 patients showed significantly reduced infections after transrectal biopsy when using antimicrobial prophylaxis as compared to placebo/control.

Recommendations Perform prostate biopsy using the transperineal approach due to the lower risk of infectious complications. Use routine surgical disinfection of the perineal skin for transperineal biopsy. Use rectal cleansing with povidone-iodine in men prior to transrectal prostate biopsy. Do not use fluoroquinolones for prostate biopsy in line with the European Commission final decision on EMEA/H/A-31/1452. Use either target prophylaxis based on rectal swab or stool culture; augmented prophylaxis (two or more different classes of antibiotics); or alternative antibiotics (e.g., fosfomycin trometamol, cephalosporin, aminoglycoside) for antibiotic prophylaxis for transrectal biopsy. Use a single oral dose of either cefuroxime or cephalexin or cephazolin as antibiotic prophylaxis for transperineal biopsy. Patients with severe penicillin allergy may be given sulphamethoxazole. Ensure that prostate core biopsies from different sites are submitted separately for processing and pathology reporting.

LE 1a

1a

1a

Strength rating* Strong Strong Strong Strong Weak

Weak

Strong

*Note on strength ratings: The above strength ratings are explained here due to the major clinical implications of these new recommendations. Although data showing the lower risk of infection via the transperineal approach is low in certainty, its statistical and clinical significance warrants its Strong rating. Strong ratings are also given for routine surgical disinfection of skin in transperineal biopsy and povidone-iodine rectal cleansing in transrectal biopsy as, although quality of data is low, the clinical benefit is high and practical application simple. A Strong rating is given for avoiding fluoroquinolones in prostate biopsy due to its legal implications in Europe.

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Figure 5.1: Prostate biopsy workflow to reduce infectious complications*

Indication for prostate biopsy?

Transperineal biopsy feasible? Yes

No

Transperineal biopsy - 1st choice (⊕⊕⊝⊝) with: • perineal cleansing • antibiotic prophylaxis

Transrectal biopsy – 2nd choice (⊕⊕⊝⊝) with: • povidone-iodine rectal preparation • antibiotic prophylaxis

Fluoroquinolones licensed?

Yes

No 1.

Targeted prophylaxis: based on rectal swab or stool cultures

2.

Augmented prophylaxis: two or more different classes of antibiotics

3.

Alternative antibiotics (⊕⊝⊝⊝):

• fosfomycin trometamol (e.g. 3 g before and 3 g 24-48 hrs after biopsy) • cephalosporin (e.g. ceftriaxone 1 g i.m.; cefixime 400 mg p.o. for 3 days starting 24 hrs before biopsy) • aminoglycoside (e.g. gentamicin 3 mg/kg i.v.; amikacin 15 mg/kg i.m.)

Duration of antibiotic prophylaxis ≥ 24 hrs (⊕⊕⊝⊝) 1.

Targeted prophylaxis (⊕⊕⊝⊝): based on rectal swab or stool cultures

2.

Augmented prophylaxis (⊕⊝⊝⊝):

3.

• Fluoroquinolone plus aminoglycoside • Fluoroquinolone plus cephalosporin

Fluoroquinolone prophylaxis

(range: ⊕⊝⊝⊝ - ⊕⊕⊝⊝)

6.1.6 General guidelines for the treatment of prostate cancer Recommendations Radiotherapeutic treatment Offer low-dose rate (LDR) brachytherapy monotherapy to patients with good urinary function and low- or good prognosis intermediate-risk localised disease. Offer LDR or high-dose rate brachytherapy boost combined with IMRT including IGRT to patients with good urinary function and intermediate-risk disease with

Strength rating Strong Strong

adverse features or high-risk disease.

6.2.1.3 Summary of evidence and guidelines for the treatment of low-risk disease Summary of evidence Systematic biopsies have been scheduled in AS protocols, the number and frequency of biopsies varied, there is no approved standard. Although per-protocol MR scans are increasingly used in AS follow-up no conclusive evidence exist in terms of their benefit/and whether biopsy may be ommitted based on the imaging findings. Personalised risk-based approaches will ultimately replace protocol-based management of patients on AS.

Recommendations Active surveillance (AS) Selection of patients Perform a mpMRI before a confirmatory biopsy if no MRI has been performed before the initial biopsy.

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Strength rating

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PROSTATE CANCER - LIMITED UPDATE 2021

Radiotherapeutic treatment Offer low-dose rate brachytherapy to patients with low-risk PCa, without a recent transurethral resection of the prostate and a good International Prostatic Symptom Score. Other therapeutic options Do not offer ADT monotherapy to asymptomatic men not able to receive any local treatment.

Strong

Strong

6.2.2.5 Guidelines for the treatment of intermediate-risk disease Recommendations Active surveillance (AS) Offer AS to highly selected patients with ISUP grade group 2 disease (i.e. < 10% pattern 4, PSA < 10 ng/mL, < cT2a, low disease extent on imaging and biopsy) accepting the potential increased risk of metastatic progression. Radiotherapeutic treatment Offer low-dose rate brachytherapy to intermediate-risk patients with ISUP grade 2 with < 33% of biopsy cores involved, without a recent transurethral resection of the prostate and with a good International Prostatic Symptom Score. For intensity-modulated radiotherapy (IMRT) plus image-guided radiotherapy (IGRT), use a total dose of 76–78 Gy or moderate hypofractionation (60 Gy/20 fx in 4 weeks or 70 Gy/28 fx in 6 weeks), in combination with short-term androgen deprivation therapy (ADT) (4 to 6 months). In patients not willing to undergo ADT, use a total dose of IMRT plus IGRT (76–78 Gy) or moderate hypofractionation (60 Gy/20 fx in 4 weeks or 70 Gy/28 fx in 6 weeks) or a combination with brachytherapy.

Strength rating Weak

Strong

Strong

Weak

6.2.3.4 Guidelines for radical treatment of high-risk localised disease Recommendation Therapeutic options outside surgery and radiotherapy Only offer ADT monotherapy to those patients unwilling or unable to receive any form of local treatment if they have a prostate-specific antigen (PSA)-doubling time < 12 months, and either a PSA > 50 ng/mL or a poorly-differentiated tumour.

Strength rating Strong

6.2.5.7 Guidelines for adjuvant treatment in pN0 and pN1 disease after radical prostatectomy Recommendation Offer adjuvant intensity-modulated radiation therapy (IMRT) plus image-guided radiation therapy (IGRT) to high-risk patients (pN0) with ISUP grade group 4–5 and pT3 ± positive margins.

Strength rating Strong

6.2.6.5 Recommendations for the management of persistent PSA after radical prostatectomy Recommendation Offer a prostate-specific membrane antigen positron emission tomography (PSMA PET) scan to men with a persistent PSA > 0.2 ng/mL if the results will influence subsequent treatment decisions.

Strength rating Weak

6.3.14 Guidelines for second-line therapy after treatment with curative intent Local salvage treatment Strength rating Recommendations for biochemical recurrence (BCR) after radical prostatectomy Offer monitoring, including prostate-specific antigen (PSA), to EAU BCR low-risk Weak patients.

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Offer early salvage intensity-modulated radiotherapy plus image-guided radiotherapy to men with two consecutive PSA rises. A negative PET/CT scan should not delay salvage radiotherapy (SRT), if otherwise indicated. Do not wait for a PSA threshold before starting treatment. Once the decision for SRT has been made, SRT (at least 66 Gy) should be given as soon as possible. Recommendations for BCR after radiotherapy Offer monitoring, including prostate-specific antigen (PSA), to EAU Low-Risk BCR patients. Only offer salvage radical prostatectomy (RP), brachytherapy, high-intensity focused ultrasound, or cryosurgical ablation to highly selected patients with biopsy proven local recurrence within a clinical trial setting or well-designed prospective cohort study undertaken in experienced centres.

Strong Strong Strong

Weak Strong

6.4.9 Guidelines for the first-line treatment of metastatic disease Recommendations Discuss combination therapy including ADT plus systemic therapy with all M1 patients. Do not offer ADT monotherapy to patients whose first presentation is M1 disease if they have no contraindications for combination therapy and have a sufficient life expectancy to benefit from combination therapy and are willing to accept the increased risk of side effects. Do not offer ADT combined with surgery to M1 patients outside of clinical trials. Only offer metastasis-directed therapy to M1 patients within a clinical trial setting or well-designed prospective cohort study.

Strength rating Strong Strong

Strong Strong

6.5.14 Summary of evidence and guidelines for life-prolonging treatments of castrate-resistant disease Recommendations Treat patients with mCRPC with life-prolonging agents. Offer mCRPC patients somatic and/or germline molecular testing as well as testing for mismatch repair deficiencies or microsatellite instability.

Strength rating Strong Strong

6.5.15 Guidelines for systematic treatments of castrate-resistant disease Recommendations Base the choice of treatment on the performance status, symptoms, co-morbidities, location and extent of disease, genomic profile, patient preference, and on the previous treatment for hormone-sensitive metastatic PCa (mHSPC) (alphabetical order: abiraterone, cabazitaxel, docetaxel, enzalutamide, olaparib, radium-223, sipuleucel-T). Offer patients with mCRPC who are candidates for cytotoxic therapy and are chemotherapy naïve docetaxel with 75 mg/m2 every 3 weeks. Offer patients with mCRPC and progression following docetaxel chemotherapy further life-prolonging treatment options, which include abiraterone, cabazitaxel, enzalutamide, radium-223 and olaparib in case of DNA homologous recombination repair (HRR) alterations. Base further treatment decisions of mCRPC on performance status, previous treatments, symptoms, co-morbidities, genomic profile, extent of disease and patient preference. Offer abiraterone or enzalutamide to patients previously treated with one or two lines of chemotherapy. Avoid sequencing of androgen receptor targeted agents, Offer chemotherapy to patients previously treated with abiraterone or enzalutamide. Offer cabazitaxel to patients previously treated with docetaxel. Recommendations for BCR after radiotherapy Offer poly(ADP-ribose) polymerase (PARP) inhibitors to pretreated mCRPC patients with relevant DNA repair gene mutations.

14

Strength rating Strong

Strong Strong

Strong

Strong Weak Strong Strong Strong

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7.2.6 Guidelines for follow-up during hormonal treatment Recommendations In M1 patients, schedule follow-up at least every 3 to 6 months. In patients on long-term androgen deprivation therapy (ADT), measure initial bone mineral density to assess fracture risk. During follow-up of patients receiving ADT, check PSA and testosterone levels and monitor patients for symptoms associated with metabolic syndrome as a side effect of ADT. As a minimum requirement, include a disease-specific history, haemoglobin, serum creatinine, alkaline phosphatase, lipid profiles and HbA1c level measurements. When disease progression is suspected, restaging is needed and the subsequent follow up adapted/individualised. In M1 patients perform regular imaging (CT and bone scan) even without PSA progression. In patients with suspected progression, assess the testosterone level. By definition, castration- resistant PCa requires a testosterone level < 50 ng/dL (< 1.7 nM/L).

Strength rating Strong Strong Strong

Strong Weak Strong

8.3.2.5 Guidelines for quality of life in men undergoing systemic treatments Recommendations Strength rating Advise men on ADT to maintain a healthy weight and diet, to stop smoking, Strong reduce alcohol to < 2 units daily and have yearly screening for diabetes and hypercholesterolemia. Ensure that calcium and vitamin D meet recommended levels. Offer anti-resorptive therapy to men on long term ADT with either a BMD T-score of Strong 79 years [13]. The incidence of PCa diagnosis varies widely between different geographical areas, being highest in Australia/New Zealand and Northern America (age-standardised rates [ASR] per 100,000 of 111.6 and 97.2, respectively), and in Western and Northern Europe (ASRs of 94.9 and 85, respectively), largely due to the use of prostate-specific antigen (PSA) testing and the aging population. The incidence is low in Eastern and South-Central Asia (ASRs of 10.5 and 4.5, respectively). Rates in Eastern and Southern Europe were low but have shown a steady increase [11, 12]. Incidence and disease stage distibution patters follow (inter)national organisations‘ recommendations (see Section 5.1) [14]. There is relatively less variation in mortality rates worldwide, although rates are generally high in populations of African descent (Caribbean: ASR of 29 and Sub-Saharan Africa: ASRs ranging between 19 and 14), intermediate in the USA and very low in Asia (South-Central Asia: ASR of 2.9) [11].

3.2

Aetiology

3.2.1 Family history/hereditary prostate cancer Family history and ethnic background are associated with an increased PCa incidence suggesting a genetic predisposition [15, 16]. Only a small subpopulation of men with PCa have true hereditary disease. Hereditary PCa (HPCa) is associated with a six to seven year earlier disease onset but the disease aggressiveness and clinical course does not seem to differ in other ways [15, 17]. In a large USA population database, HPCa (in 2.18% of participants) showed a relative risk (RR) of 2.30 for diagnosis of any PCa, 3.93 for early-onset PCa, 2.21 for lethal PCa, and 2.32 for clinically significant PCa (csPCa) [18]. These increased risks of HPCa were higher than for familial PCa (> 2 first- or second-degree relatives with PCa on the same side of the pedigree), or familial syndromes such as hereditary breast and ovarian cancer and Lynch syndrome. The probability of high-risk PCa at age 65 was 11.4% (vs. a population 16

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risk of 1.4%) in a Swedish population-based study [19]. 3.2.1.1 Germline mutations and prostate cancer Genome-wide association studies have identified more than 100 common susceptibility loci contributing to the risk for PCa [20-22]. Clinical cohort studies have reported rates of 15% to 17% of germline mutations independent of stage [23, 24]. Giri et al. studied clinical genetic data from men with PCa unselected for metastatic disease undergoing multigene testing across the US [23]. The authors found that 15.6% of men with PCa have pathogenic variants identified in genes tested (BRCA1, BRCA2, HOXB13, MLH1, MSH2, PMS2, MSH6, EPCAM, ATM, CHEK2, NBN, and TP53), and 10.9% of men have germline pathogenic variants in DNA repair genes (see Table 5.2). Pathogenic variants were most commonly identified in BRCA2 (4.5%), CHEK2 (2.2%), ATM (1.8%), and BRCA1 (1.1%) [23]. Presence of Gleason 8 or higher was significantly associated with DNA repair pathogenic variants (OR 1.85 [95% CI: 1.22–2.80], p = 0.004) [23]. Nicolosi and colleagues reported frequency and distribution of positive germline variants in 3,607 unselected PCa patients and found that 620 (17.2%) had a pathogenic germline variant [24]. The percentage of BRCA1/2 mutations in this study was 6%. Among unselected men with metastatic PCa, an incidence of 11.8% was found for germline mutations in genes mediating DNA-repair processes [25]. Most mutations were seen in BRCA2 (5.35%), ATM (1.6%), CHEK2 (1.9%), BRCA1 (0.9%), and PALB2 (0.4%). Targeted genomic analysis of genes associated with an increased risk of PCa could offer options to identify families at high risk [26, 27]. Nyberg et al. presented results of a prospective cohort study of male BRCA1 and BRCA2 carriers and their PCa risk confirming BRCA2 association with aggressive PCa [28]. Mutations in the PCa cluster region of the BRCA2 gene may increase the PCa risk in particular. Castro and colleagues analysed the outcomes of 2,019 patients with PCa (18 BRCA1 carriers, 61 BRCA2 carriers, and 1,940 non-carriers). Prostate cancers with germline BRCA1/2 mutations were more frequently associated with ISUP > 4, T3/T4 stage, nodal involvement, and metastases at diagnosis than PCa in non-carriers [29]. BReast-CAncer susceptibility gene mutation carriers were reported to have worse outcome when compared to non-carriers after local therapy [30]. In a retrospective study of 313 patients who died of PCa and 486 patients with low-risk localised PCa, the combined BRCA1/2 and ATM mutation carrier rate was significantly higher in lethal PCa patients (6.07%) than in localised PCa patients (1.44%) [31]. The Identification of Men With a Genetic Predisposition to ProstAte Cancer (IMPACT) study, which evaluates targeted PCa screening (annually, biopsy recommended if PSA > 3.0 ng/mL) using PSA in men aged 40–69 years with germline BRCA1/2 mutations, has recently reported interim results [32]. The authors found that after 3 years of screening, BRCA2 mutation carriers were associated with a higher incidence of PCa, a younger age of diagnosis, and more clinically significant tumours compared with non-carriers. The influence of BRCA1 mutations on PCa remained unclear. No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 non-carriers. Limitations of the IMPACT study include the lack of multiparametric magnetic resonance imaging (mpMRI) data and targeted biopsies as it was initiated before that era. Similarly, Mano et al. reported on an Israeli cohort in which men with BRCA1 and BRCA2 mutations had a significantly higher incidence of malignant disease. In contrast to findings of the IMPACT study, the rate of PCa among BRCA1 carriers was more than twice as high (8.6% vs. 3.8%) compared to the general population [33]. 3.2.2 Risk factors A wide variety of exogenous/environmental factors have been discussed as being associated with the risk of developing PCa or as being aetiologically important for the progression from latent to clinical PCa [34]. Japanese men have a lower PCa risk compared to men from the Western world. However, as Japanese men move from Japan to California, their risk of PCa increases, approaching that of American men, implying a role of environmental or dietary factors [35]. However, currently there are no known effective preventative dietary or pharmacological interventions. 3.2.2.1 Metabolic syndrome The single components of metabolic syndrome (MetS) hypertension (p = 0.035) and waist circumference > 102 cm (p = 0.007) have been associated with a significantly greater risk of PCa, but in contrast, having > 3 components of MetS is associated with a reduced risk (OR: 0.70, 95% CI: 0.60–0.82) [36, 37]. 3.2.2.1.1 Diabetes/metformin On a population level, metformin users (but not other oral hypoglycaemic agents) were found to be at a decreased risk of PCa diagnosis compared with never-users (adjusted OR: 0.84, 95% CI: 0.74–0.96) [38]. PROSTATE CANCER - LIMITED UPDATE 2021

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In 540 diabetic participants of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study, metformin use was not significantly associated with PCa and therefore not advised as a preventive measure (OR: 1.19, p = 0.50) [39]. The ongoing Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial assesses metformin use in advanced PCa (Arm K) [40]. 3.2.2.1.2 Cholesterol/statins A meta-analysis of 14 large prospective studies did not show an association between blood total cholesterol, highdensity lipoprotein cholesterol, low-density lipoprotein cholesterol levels and the risk of either overall PCa or highgrade PCa [36]. Results from the REDUCE study also did not show a preventive effect of statins on PCa risk [39]. 3.2.2.1.3 Obesity Within the REDUCE study, obesity was associated with lower risk of low-grade PCa in multivariable analyses (OR: 0.79, p = 0.01), but increased risk of high-grade PCa (OR: 1.28, p = 0.042) [41]. This effect seems mainly explained by environmental determinants of height/body mass index (BMI) rather than genetically elevated height or BMI [42]. 3.2.2.2 Dietary factors The association between a wide variety of dietary factors and PCa have been studied (Table 3.1). Table 3.1: Dietary factors that have been associated with PCa Alcohol

Dairy Fat

Tomatoes (lycopenes/ carotenes) Meat Phytoestrogens Soy (phytoestrogens [isoflavones/ coumestans]) Vitamin D

High alcohol intake, but also total abstention from alcohol has been associated with a higher risk of PCa and PCa-specific mortality [43]. A meta-analysis shows a doseresponse relationship with PCa [44]. A weak correlation between high intake of protein from dairy products and the risk of PCa was found [45]. No association between intake of long-chain omega-3 poly-unsaturated fatty acids and PCa was found [46]. A relation between intake of fried foods and risk of PCa may exist [47]. A trend towards a favourable effect of tomato intake (mainly cooked) and lycopenes on PCa incidence has been identified in meta-analyses [48, 49]. Randomised controlled trials comparing lycopene with placebo did not identify a significant decrease in the incidence of PCa [50]. A meta-analysis did not show an association between red meat or processed meat consumption and PCa [51]. Phytoestrogen intake was significantly associated with a reduced risk of PCa in a meta-analysis [52]. Total soy food intake has been associated with reduced risk of PCa, but also with increased risk of advanced disease [53, 54].

A U-shaped association has been observed, with both low- and high vitamin-D concentrations being associated with an increased risk of PCa, and more strongly for high-grade disease [54, 55]. Vitamin E/Selenium An inverse association of blood, but mainly nail selenium levels (reflecting long-term exposure) with aggressive PCa have been found [56, 57]. Selenium and Vitamin E supplementation were, however, found not to affect PCa incidence [58]. 3.2.2.3 Hormonally active medication 3.2.2.3.1 5-alpha-reductase inhibitors (5-ARIs) Although it seems that 5-ARIs have the potential of preventing or delaying the development of PCa (~25%, for ISUP grade 1 cancer only), this must be weighed against treatment-related side effects as well as the potential small increased risk of high-grade PCa [59-61]. None of the available 5-ARIs have been approved by the European Medicines Agency (EMA) for chemoprevention. 3.2.2.3.2 Testosterone Hypogonadal men receiving testosterone supplements do not have an increased risk of PCa [62]. A pooled analysis showed that men with very low concentrations of free testosterone (lowest 10%) have a below average risk (OR: 0.77) of PCa [63].

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3.2.2.4 Other potential risk factors A significantly higher rate of ISUP > 2 PCas (hazard ratio [HR]: 4.04) was found in men with inflammatory bowel disease when compared to the general population [64]. Balding was associated with a higher risk of PCa death [65]. Gonorrhoea was significantly associated with an increased incidence of PCa (OR: 1.31, 95% CI: 1.14–1.52) [66]. Occupational exposure may also play a role, based on a meta-analysis which revealed that night-shift work is associated with an increased risk (2.8%, p = 0.030) of PCa [67]. Current cigarette smoking was associated with an increased risk of PCa death (RR: 1.24, 95% CI: 1.18–1.31) and with aggressive tumour features and worse prognosis, even after cessation [68, 69]. A meta-analysis on Cadmium (Cd) found a positive association (magnitude of risk unknown due to heterogeneity) between high Cd exposure and risk of PCa for occupational exposure, but not for non-occupational exposure, potentially due to higher Cd levels during occupational exposure [70]. Men positive for human papillomavirus-16 may be at increased risk [71]. Plasma concentration of the estrogenic insecticide chlordecone is associated with an increase in the risk of PCa (OR: 1.77 for highest tertile of values above the limit of detection) [72]. A number of other factors previously linked to an increased risk of PCa have been disproved including vasectomy [73] and self-reported acne [74]. There are conflicting data about the use of aspirin or nonsteroidal anti-inflammatory drugs and the risk of PCa and mortality [75, 76]. Ultraviolet radiation exposure decreased the risk of PCa (HR: 0.91, 95% CI: 0.88–0.95) [77]. A review found a small but protective association of circumcision status with PCa [78]. Higher ejaculation frequency (> 21 times a month vs. 4 to 7 times) has been associated with a 20% lower risk of PCa [79]. The associations with PCa identified to date lack evidence for causality. As a consequence there is no data to suggest effective preventative strategies. 3.2.3

Summary of evidence for epidemiology and aetiology

Summary of evidence Prostate cancer is a major health concern in men, with incidence mainly dependent on age. Genetic factors are associated with risk of (aggressive) PCa. A variety of exogenous/environmental factors have been associated with PCa incidence and prognosis. Selenium or vitamin-E supplements have no beneficial effect in preventing PCa. In hypogonadal men, testosterone supplements do not increase the risk of PCa. No specific preventive or dietary measures are recommended to reduce the risk of developing PCa.

4.

CLASSIFICATION AND STAGING SYSTEMS

4.1

Classification

LE 3 3 3 2a 2 1a

The objective of a tumour classification system is to combine patients with a similar clinical outcome. This allows for the design of clinical trials on relatively homogeneous patient populations, the comparison of clinical and pathological data obtained from different hospitals across the world, and the development of recommendations for the treatment of these patient populations. Throughout these Guidelines the 2017 Tumour, Node, Metastasis (TNM) classification for staging of PCa (Table 4.1) [80] and the EAU risk group classification, which is essentially based on D’Amico’s classification system for PCa, are used (Table 4.2) [81]. The latter classification is based on the grouping of patients with a similar risk of biochemical recurrence (BCR) after radical prostatectomy (RP) or external beam radiotherapy (EBRT). Multiparametric resonance imaging and targeted biopsy may cause a stage shift in risk classification systems [82].

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Table 4.1: Clinical Tumour Node Metastasis (TNM) classification of PCa [80] T - Primary Tumour (stage based on digital rectal examination [DRE] only) TX Primary tumour cannot be assessed T0 No evidence of primary tumour T1 Clinically inapparent tumour that is not palpable T1a Tumour incidental histological finding in 5% or less of tissue resected T1b Tumour incidental histological finding in more than 5% of tissue resected T1c Tumour identified by needle biopsy (e.g. because of elevated prostate-specific antigen [PSA]) T2 Tumour that is palpable and confined within the prostate T2a Tumour involves one half of one lobe or less T2b Tumour involves more than half of one lobe, but not both lobes T2c Tumour involves both lobes T3 Tumour extends through the prostatic capsule T3a Extracapsular extension (unilateral or bilateral) T3b Tumour invades seminal vesicle(s) T4 Tumour is fixed or invades adjacent structures other than seminal vesicles: external sphincter, rectum, levator muscles, and/or pelvic wall N - Regional (pelvic) Lymph Nodes1 NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis M - Distant Metastasis2 M0 No distant metastasis M1 Distant metastasis M1a Non-regional lymph node(s) M1b Bone(s) M1c Other site(s) 1 2

Metastasis no larger than 0.2 cm can be designated pNmi. When more than one site of metastasis is present, the most advanced category is used. (p)M1c is the most advanced category.

Clinical T stage only refers to DRE findings; local imaging findings are not considered in the TNM classification. Pathological staging (pTNM) is based on histopathological tissue assessment and largely parallels the clinical TNM, except for clinical stage T1 and the T2 substages. Pathological stages pT1a/b/c do not exist and histopathologically confirmed organ-confined PCas after RP are pathological stage pT2. The current Union for International Cancer Control (UICC) no longer recognises pT2 substages [80].

4.2

Gleason score and International Society of Urological Pathology 2014 grade

In the original Gleason grading system, 5 Gleason grades (ranging from 1–5) based on histological tumour architecture were distinguished, but in the 2005 and subsequent 2014 International Society of Urological Pathology (ISUP) Gleason score (GS) modifications Gleason grades 1 and 2 were eliminated [83, 84]. The 2005 ISUP modified GS of biopsy-detected PCa comprises the Gleason grade of the most extensive (primary) pattern, plus the second most common (secondary) pattern, if two are present. If one pattern is present, it needs to be doubled to yield the GS. For three grades, the biopsy GS comprises the most common grade plus the highest grade, irrespective of its extent. The grade of intraductal carcinoma should also be incorporated in the GS [85]. In addition to reporting of the carcinoma features for each biopsy, an overall (or global) GS based on the carcinoma-positive biopsies can be provided. The global GS takes into account the extent of each grade from all prostate biopsies. The 2014 ISUP endorsed grading system [84, 86] limits the number of PCa grades, ranging them from 1 to 5 (see Table 4.2), in order to: 1. align the PCa grading with the grading of other carcinomas; 2. eliminate the anomaly that the most highly differentiated PCas have a GS 6; 3. to further define the clinically highly significant distinction between GS 7(3+4) and 7(4+3) PCa [87].

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Table 4.2: EAU risk groups for biochemical recurrence of localised and locally advanced prostate cancer Definition Low-risk PSA < 10 ng/mL

Intermediate-risk PSA 10-20 ng/mL

High-risk PSA > 20 ng/mL

any PSA

and GS < 7 (ISUP grade 1) or GS 7 (ISUP grade 2/3) or GS > 7 (ISUP grade 4/5) any GS (any ISUP grade) and cT1-2a

or cT2b

or cT2c

Localised

cT3-4 or cN+ Locally advanced

GS = Gleason score; ISUP = International Society for Urological Pathology; PSA = prostate-specific antigen. Table 4.3: International Society of Urological Pathology 2014 grade (group) system Gleason score

ISUP grade

2-6

1

7 (3+4)

2

7 (4+3)

3

8 (4+4 or 3+5 or 5+3)

4

9-10

5

4.3

Prognostic relevance of stratification

Comparison of various risk stratification tools using death of disease as outcome parameter revealed that 3-tiered systems, including the EAU and D’Amico risk classification, were inferior to the MSKCC nomograms, the CAPRA score and the 5-tiered CPG system [88]. Similarly, using death of disease as outcome parameter a 9-tier risk clinical prognostic stage group system, based on age, cT, cN, ISUP grade, percentage positive cores and PSA as input variables further improved risk stratification in patients treated by surgery or radiotherapy (RT) [89]. A more precise stratification of the clinically heterogeneous subset of intermediate-risk group patients could provide a better framework for their management. The adoption of the current ISUP grading system, defining the split-up of GS 7 cancers into ISUP grade 2 (primary Gleason grade 3) and ISUP grade 3 (primary Gleason grade 4) because of their distinct prognostic impact strengthens such a separation of the intermediate-risk group into a low-intermediate (ISUP grade 2) and high-intermediate (ISUP grade 3) risk group [86] (see Section 6.2.2). Emerging clinical data support this distinction between favourable- and unfavourable-risk patient categories within the intermediate-risk group [87, 90].

4.4

Guidelines for classification and staging systems

Recommendations Strength rating Use the Tumour, Node, Metastasis (TNM) classification for staging of PCa. Strong Use the International Society of Urological Pathology (ISUP) 2014 system for grading of PCa. Strong

5.

DIAGNOSTIC EVALUATION

5.1

Screening and early detection

5.1.1 Screening Population or mass screening is defined as the ‘systematic examination of asymptomatic men (at risk)’ and is usually initiated by health authorities. The co-primary objectives are: • reduction in mortality due to PCa; • a maintained QoL as expressed by QoL-adjusted gain in life years (QALYs). Prostate cancer mortality trends range widely from country to country in the industrialised world [91]. Mortality due to PCa has decreased in most Western nations but the magnitude of the reduction varies between countries. Currently, screening for PCa still remains one of the most controversial topics in the urological literature [92].

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Initial widespread aggressive screening in USA was associated with a decrease in mortality [93]. In 2012 the US Preventive Services Task Force (USPSTF) released a recommendation against PSA-based screening [94], which was adopted in the 2013 AUA Guidelines [95] and resulted in a reduction in the use of PSA for early detection [96]. This reduction in the use of PSA testing was associated with higher rates of advanced disease at diagnosis (e.g., a 6% increase in the number of patients with metastatic PCa [14, 97-100]. While PCa mortality had decreased for two decades since the introduction of PSA testing [101], the incidence of advanced disease and, possibly, cancer-related mortality slowly increased from 2008 and accelerated in 2012 [102]. Moreover, additional evidence suggests a long-term benefit of PSA population screening in terms of reduction of cancer-specific mortality [103, 104]. However, the temporal relationship between PSA testing and decreased mortality, as well as a rising mortality following immediately after the USPSTF and AUA Guidelines recommendation against PSA testing questions the direct causative link between both points. In 2017 the USPSTF issued an updated statement suggesting that men aged 55–69 should be informed about the benefits and harms of PSA-based screening as this might be associated with a small survival benefit. The USPSTF has now upgraded this recommendation to a grade C [105], from a previous grade ‘D’ [105-107]. They highlighted the fact that the decision to be screened should be an individual one. The grade D recommendation remains in place for men over 70 years old. This represents a major switch from discouraging PSA-based screening (grade D) to offering early diagnosis to selected men depending on individual circumstances. A comparison of systematic and opportunistic screening suggested over-diagnosis and mortality reduction in the systematic screening group compared to a higher over-diagnosis with a marginal survival benefit, at best, in the opportunistic screening regimen [108]. A Cochrane review published in 2013 [109], which has since been updated [110], presents the main overview to date. The findings of the updated publication (based on a literature search until April 3, 2013) are almost identical to the 2009 review: • Screening is associated with an increased diagnosis of PCa (RR: 1.3, 95% CI: 1.02–1.65). • Screening is associated with detection of more localised disease (RR: 1.79, 95% CI: 1.19–2.70) and less advanced PCa (T3–4, N1, M1) (RR: 0.80, 95% CI: 0.73–0.87). • From the results of 5 RCTs, randomising more than 341,000 men, no PCa-specific survival benefit was observed (RR: 1.00, 95% CI: 0.86–1.17). This was the main endpoint in all trials. • From the results of four available RCTs, no overall survival (OS) benefit was observed (RR: 1.00, 95% CI: 0.96–1.03). The included studies applied a range of different screening measures and testing intervals in patients who had ondergone prior PSA testing, to various degrees. None included the use of risk calculators, MRI prior to biopsy (vs. a single PSA threshold) or AS (as an alternative to RP) which no longer reflects current standard practice. The diagnostic tool (i.e. biopsy procedure) was not associated with increased mortality within 120 days after biopsy in screened men as compared to controls in the two largest population-based screening populations (ERSPC and PLCO), in contrast to a 120-day mortality rate of 1.3% in screened vs. 0.3% in controls, respectively, in a Canadian population-based screening study [111]. Increased diagnosis has historically led to over-treatment with associated side effects. However, despite this, the impact on the patient’s overall QoL is still unclear. Population level screening has never been shown to be detrimental [112-114]. Nevertheless, all these findings have led to strong advice against systematic population-based screening in most countries, including those in Europe. In case screening is considered, a single PSA test is not enough based on the Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) trial. The CAP trial evaluated a single PSA screening vs. controls not undergoing PSA screening on PCa detection in men aged 50 to 69 years old. The single PSA screening intervention detected more low-risk PCa cases but had no significant effect on PCa mortality after a median follow-up of 10 years [115]. Since 2013, the European Randomized Study of Screening for Prostate Cancer (ERSPC) data have been updated with 16 years of follow-up (see Table 5.1) [116]. The key message is that with extended followup, the mortality reduction remains unchanged (21%, and 29% after non-compliance adjustment). However the number needed to screen (NNS) and to treat is decreasing, and is now below the NNS observed in breast cancer trials [116, 117]. Long-term follow-up of the PLCO (Prostate, Lung, Colon, Ovarian cancer screening trial) showed no survival benefit for screening at a median follow-up of 16.7 years but a significant 17% increase in Gleason score 2–6 cancers and 11% decrease in Gleason score 8–10 cancers [118].

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Table 5.1: Follow-up data from the ERSPC study [116] Years of follow-up

Number needed to screen

Number needed to treat

9

1,410

48

11

979

35

13

781

27

16

570

18

5.1.2 Early detection An individualised risk-adapted strategy for early detection may still be associated with a substantial risk of over-diagnosis. It is essential to remember that breaking the link between diagnosis and active treatment is the only way to decrease over-treatment, while still maintaining the potential benefit of individual early diagnosis for men requesting it [16, 119]. Men at elevated risk of having PCa are those > 50 years [120] or at age > 45 years with a family history of PCa (either paternal or maternal) [121] or of African descent [122, 123]. Men of African descent are more likely to be diagnosed with more advanced disease [124] and upgrade was more frequent after prostatectomy as compared to Caucasian men (49% vs. 26%) [125]. Germline mutations are associated with an increased risk of the development of aggressive PCa, i.e. BRCA2 [126, 127]. Prostate-specific antigen screening in male BRCA1 and 2 carriers detected more significant cancers at a younger age compared to non-mutation carriers [32, 33]. Men with a baseline PSA < 1 ng/mL at 40 years and < 2 ng/mL at 60 years are at decreased risk of PCa metastasis or death from PCa several decades later [128, 129]. The use of DRE alone in the primary care setting had a sensitivity and specificity below 60%, possibly due to inexperience, and can therefore not be recommended to exclude PCa [130]. Informed men requesting an early diagnosis should be given a PSA test and undergo a DRE [131]. Prostate-specific antigen measurement and DRE need to be repeated [115], but the optimal intervals for PSA testing and DRE follow-up are unknown as they varied between several prospective trials. A risk-adapted strategy might be a consideration, based on the initial PSA level. This could be every 2 years for those initially at risk, or postponed up to 8 to 10 years in those not at risk with an initial PSA < 1 ng/mL at 40 years and a PSA < 2 ng/mL at 60 years of age and a negative family history [132]. An analysis of ERSPC data supports a recommendation for an 8-year screening interval in men with an initial PSA concentration < 1 μg/L; fewer than 1% of men with an initial PSA concentration < 1 ng/mL were found to have a concentration above the biopsy threshold of 3 μg/L at 4-year follow-up; the cancer detection rate by 8 years was close to 1% [133]. The long-term survival and QoL benefits of extended PSA re-testing (every 8 years) remain to be proven at a population level. Data from the Goteborg arm of the ERSPC trial suggest that the age at which early diagnosis should be stopped remains controversial, but an individual’s life expectancy must definitely be taken into account. Men who have less than a 15-year life expectancy are unlikely to benefit, based on data from the Prostate Cancer Intervention Versus Observation Trial (PIVOT) and the ERSPC trials. Furthermore, although there is no simple tool to evaluate individual life expectancy; co-morbidity is at least as important as age. A detailed review can be found in Section 5.4 ‘Estimating life expectancy and health status’ and in the SIOG Guidelines [134]. Multiple tools are now available to determine the need for a biopsy to establish the diagnosis of a PCa, including imaging by MRI, if available (see Section 5.2.4). Urine and serum biomarkers as well as tissue-based biomarkers have been proposed for improving detection and risk stratification of PCa patients, potentially avoiding unnecessary biopsies. However, further studies are necessary to validate their efficacy [135]. At present there is too limited data to implement these markers into routine screening programmes (see Section 5.2.3). Risk calculators may be useful in helping to determine (on an individual basis) what the potential risk of cancer may be, thereby reducing the number of unnecessary biopsies. Several tools developed from cohort studies are available including: • the PCPT cohort: PCPTRC 2.0 http://myprostatecancerrisk.com/; • the ERSPC cohort: http://www.prostatecancer-riskcalculator.com/seven-prostate-cancer-risk-calculators; An updated version was presented in 2017 including prediction of low and high risk now also based on the ISUP grading system and presence of cribriform growth in histology [136]. • a local Canadian cohort: https://sunnybrook.ca/content/?page=asure-calc (among others). PROSTATE CANCER - LIMITED UPDATE 2021

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Since none of these risk calculators has clearly shown superiority, it remains a personal decision as to which one to use [137]. A comparative analysis showed risk calculators containing MRI to be most predictive, however, regional modifications may be required before implementation [138]. 5.1.3 Genetic testing for inherited prostate cancer Increasing evidence supports the implementation of genetic counselling and germline testing in early detection and PCa management. Several commercial screening panels are now available to assess main PCa risk genes [139]. However, it remains unclear when germline testing should be considered and how this may impact localised and metastatic disease management. Germline BRCA1 and BRCA2 mutations occur in approximately 0.2% to 0.3% of the general population [140]. It is important to understand the difference between somatic testing, which is performed on the tumour, and germline testing, which is performed on blood or saliva and identifies inherited mutations. Genetic counselling is required prior to and after undergoing germline testing. Germline mutations can drive the development of aggressive PCa. Therefore, the following men with a personal or family history of PCa or other cancer types arising from DNA repair gene mutations should be considered for germline testing: • Men with metastatic PCa; • Men with high-risk PCa and a family member diagnosed with PCa at age < 60 years; • Men with multiple family members diagnosed with csPCa at age < 60 years or a family member who died from PCa cancer; • Men with a family history of high-risk germline mutations or a family history of multiple cancers on the same side of the family. Further research in this field (including not so well-known germline mutations) is needed to develop screening, early detection and treatment paradigms for mutation carriers and family members. Table 5.2: Germline mutations in DNA repair genes associated with increased risk of prostate cancer Gene BRCA2

Location Prostate Cancer risk Findings 13q12.3 - 2.5 to 4.6 [141, 142] • up to 12 % of men with metastatic PCa harbour germline mutations in 16 genes (including BRCA2 -P  Ca at 55 years or [5.3%]) [25] under: RR: 8–23 • 2% of men with early-onset PCa harbour germline [141, 143] mutations in the BRCA2 gene [141] • BRCA2 germline alteration is an independent predictor of metastases and worse PCa-specific survival [29, 144] ATM 11q22.3 RR: 6.3 for metastatic • higher rates of lethal PCa among mutation carriers [31] prostate [25] • up to 12% of men with metastatic PCa harbour germline mutations in 16 genes (including ATM [1.6%]) [25] CHEK2 22q12.1 OR 3.3 [145, 146] • up to 12% of men with metastatic PCa harbour germline mutations in 16 genes (including CHEK2 [1.9%]) [25] BRCA1 17q21 RR: 1.8–3.8 at 65 • higher rates of lethal PCa among mutation carriers [31] years or under • up to 12% of men with metastatic PCa harbour germline mutations in 16 genes (including BRCA1 [0.9%]) [25] [147, 148] HOXB13 17q21.2 OR 3.4–7.9 [26, 149] • significantly higher PSA at diagnosis, higher Gleason score and higher incidence of positive surgical margins in the radical prostatectomy specimen than non-carriers [150] RR: 3.7 [151] • Mutations in MMR genes are responsible for Lynch MMR genes 3p21.3 syndrome [146] 2p21 MLH1 • MSH2 mutation carriers are more likely to develop PCa 2p16 MSH2 than other MMR gene mutation carriers [152] 7p22.2 MSH6 PMS2 BRCA2 = breast cancer gene 2; ATM = ataxia telangiectasia mutated; CHEK2 = checkpoint kinase 2; BRCA1 = breast cancer gene 1; HOXB13 = homeobox B13; MMR = mismatch repair; MLH1 = mutL homolog 1; MSH2 = mutS homolog 2; MSH6 = mutS homolog 6; PMS2 = post-meiotic segregation increased 2; PCa = prostate cancer; RR = relative risk; OR = odds ratio.

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5.1.4

Guidelines for germline testing*

Recommendations Consider germline testing in men with metastatic PCa. Consider germline testing in men with high-risk PCa who have a family member diagnosed with PCa at age < 60 years. Consider germline testing in men with multiple family members diagnosed with PCa at age < 60 years or a family member who died from PCa. Consider germline testing in men with a family history of high-risk germline mutations or a family history of multiple cancers on the same side of the family.

Strength rating weak weak weak weak

*Genetic counseling is required prior to germline testing. 5.1.5

Guidelines for screening and early detection

Recommendations Do not subject men to prostate-specific antigen (PSA) testing without counselling them on the potential risks and benefits. Offer an individualised risk-adapted strategy for early detection to a well-informed man and a life-expectancy of at least 10 to 15 years. Offer early PSA testing to well-informed men at elevated risk of having PCa: • men from 50 years of age; • men from 45 years of age and a family history of PCa; • men of African descent from 45 years of age; • men carrying BRCA2 mutations from 40 years of age. Offer a risk-adapted strategy (based on initial PSA level), with follow-up intervals of 2 years for those initially at risk: • men with a PSA level of > 1 ng/mL at 40 years of age; • men with a PSA level of > 2 ng/mL at 60 years of age; Postpone follow-up to 8 years in those not at risk. Stop early diagnosis of PCa based on life expectancy and performance status; men who have a life-expectancy of  0.2 mL. In ~18% of cases, PCa is detected by suspect DRE alone, irrespective of PSA level [153]. A suspect DRE in patients with a PSA level < 2 ng/mL has a positive predictive value (PPV) of 5–30% [154]. An abnormal DRE is associated with an increased risk of a higher ISUP grade and is an indication for biopsy [155, 156]. 5.2.2 Prostate-specific antigen The use of PSA as a serum marker has revolutionised PCa diagnosis [157]. Prostate-specific antigen is organ but not cancer specific; therefore, it may be elevated in benign prostatic hypertrophy (BPH), prostatitis and other non-malignant conditions. As an independent variable, PSA is a better predictor of cancer than either DRE or transrectal ultrasound (TRUS) [158]. There are no agreed standards defined for measuring PSA [159]. It is a continuous parameter, with higher levels indicating greater likelihood of PCa. Many men may harbour PCa despite having low serum PSA [160]. Table 5.3 demonstrates the occurrence of ISUP > grade 2 PCa at low PSA levels, precluding an optimal PSA threshold for detecting non-palpable but csPCa. The use of nomograms may help in predicting indolent PCa [161].

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Table 5.3: Risk of PCa identified by systemic PCa biopsy in relation to low PSA values [160] PSA level (ng/mL) 0.0–0.5 0.6–1.0 1.1–2.0 2.1–3.0 3.1–4.0

Risk of PCa (%) 6.6 10.1 17.0 23.9 26.9

Risk of ISUP grade > 2 PCa (%) 0.8 1.0 2.0 4.6 6.7

5.2.2.1 PSA density Prostate-specific antigen density is the level of serum PSA divided by the prostate volume. The higher the PSA density, the more likely it is that the PCa is clinically significant (see Section 6.2.1 - Treatment of low-risk disease). 5.2.2.2 PSA velocity and doubling time There are two methods of measuring PSA kinetics: • PSA velocity (PSAV): absolute annual increase in serum PSA (ng/mL/year) [162]; • PSA doubling time (PSA-DT): which measures the exponential increase in serum PSA over time [163]. Prostate-specific antigen velocity and PSA-DT may have a prognostic role in treating PCa but have limited diagnostic use because of background noise (total prostate volume, and BPH), different intervals between PSA determinations, and acceleration/deceleration of PSAV and PSA-DT over time [164]. These measurements do not provide additional information compared with PSA alone [165-168]. Prostate-specific antigen kinetics is mainly exponential, especially during relapse. Two methods have been described to calculate PSA-DT: the 2 -points and the log-slope method using more PSA measurements [169]. The latter is considered more accurate as it eliminates inter- and intra-essay variations as well as any physiological variations and potential imprecise measurements of low values [170, 171]. To obtain a reliable evaluation, at least 3 PSA measurements must be available, collected four weeks apart as a minimum from the same clinical laboratory [164]. A minimum increase of between 0.2 and 0.4 ng/mL is required [172]. As PSA-DT values may fluctuate over time in some men, only values obtained over the past 12 months should be considered to assess disease course [164]. The Memorial Sloan Kettering Cancer Center PSA Doubling Time calculator is one of the most widely used tools: https://www.mskcc.org/nomograms/prostate/psa_ doubling_time. 5.2.2.3 Free/total PSA ratio Free/total (f/t) PSA must be used cautiously because it may be adversely affected by several pre-analytical and clinical factors (e.g., instability of free PSA at 4°C and room temperature, variable assay characteristics, and concomitant BPH in large prostates) [173]. Prostate cancer was detected in men with a PSA 4–10 ng/mL by biopsy in 56% of men with f/t PSA < 0.10, but in only 8% with f/t PSA > 0.25 ng/mL [174]. A systematic review including 14 studies found a pooled sensitivity of 70% in men with a PSA of 4–10 ng/mL [175]. Free/total PSA is of no clinical use if the total serum PSA is > 10 ng/mL or during follow-up of known PCa. The clinical value of f/t PSA is limited in light of the new diagnostic pathways incorporating MRI (see Section 5.2.4.2). 5.2.3 Biomarkers in prostate cancer 5.2.3.1 Blood based biomarkers: PHI/4K score/IsoPSA Several assays measuring a panel of kallikreins in serum or plasma are now commercially available, including the U.S. Food and Drug Administration (FDA) approved Prostate Health Index (PHI) test (combining free and total PSA and the [-2]pro-PSA isoform [p2PSA]), and the four kallikrein (4K) score test (measuring free, intact and total PSA and kallikrein-like peptidase 2 [hK2] in addition to age, DRE and prior biopsy status). Both tests are intended to reduce the number of unnecessary prostate biopsies in PSA-tested men. A few prospective multi-centre studies demonstrated that both the PHI and 4K score test out-performed f/t PSA PCa detection, with an improved prediction of csPCa in men with a PSA between 2–10 ng/mL [176-179]. In a head-to-head comparison both tests performed equally [180]. In contrast to the 4K score and PHI, which focus on the concentration of PSA isoforms, IsoPSA utilises a novel technology which focuses on the structure of PSA [181]. Using an aqueous two-phase solution, it partitions the isoforms of PSA and assesses for structural changes in PSA. In a recent multi-centre prospective validation in 271 men the assay AUC was 0.784 for high-grade vs. low-grade cancer/benign histology, which was superior to the AUCs of total PSA and percent free PSA [182].

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5.2.3.2 Urine biomarkers: PCA3/SelectMDX/Mi Prostate score (MiPS)/ExoDX Prostate cancer gene 3 (PCA3) is a prostate-specific, non-coding microRNA (mRNA) biomarker that is detectable in urine sediments obtained after three strokes of prostatic massage during DRE. The commercially available Progensa urine test for PCA3 is superior to total and percent-free PSA for the detection of PCa in men with elevated PSA as it shows significant increases in the area under the receiver-operator characteristic curve (AUC) for positive biopsies [183-186]. PCA3 score increases with PCa volume, but there are conflicting data about whether it independently predicts the ISUP grade [187]. Currently, the main indication for the Progensa test is to determine whether repeat biopsy is needed after an initially negative biopsy, but its clinical effectiveness for this purpose is uncertain [188]. Wei et al. showed 42% sensitivity at a cut-off of 60 in the primary biopsy setting with a high specificity (91%) and a PPV of 80% suggesting that the assay may be used in the primary setting [189]. The SelectMDX test is similarly based on mRNA biomarker isolation from urine. The presence of HOXC6 and DLX1 mRNA levels is assessed to provide an estimate of the risk of both presence of PCa on biopsy as well as presence of high-risk cancer [190]. TMPRSS2-ERG fusion, a fusion of the trans-membrane protease serine 2 (TMPRSS2) and the ERG gene can be detected in 50% of PCas [191]. When detection of TMPRSS2-ERG in urine was added to PCA3 expression and serum PSA (Mi(chigan)Prostate Score [MiPS]), cancer prediction improved [192]. Exosomes secreted by cancer cells may contain mRNA diagnostic for high-grade PCa [193, 194]. Use of the ExoDx Prostate IntelliScore urine exosome assay resulted in avoiding 27% of unnecessary biopsies when compared to standard of care. However, currently, both the MiPS-score and ExoDx assay are considered investigational. In 6 head-to-head comparison studies of PCA3 and PHI, only Seisen et al. found a significant difference; PCA3 detected more cancers, but for the detection of significant disease, defined as ISUP grade > 2, more than three positive cores, or > 50% cancer involvement in any core, PHI proved superior [195]. Russo et al. suggested in their systematic review that, based on moderate quality data, PHI and the 4K panel had a high diagnostic accuracy and showed similar performance in predicting the detection of significant disease with a AUC of 0.82 and 0.81, respectively [196]. However, in the screening population of the ERSPC study the use of both PCA3 and 4K panel when added to the risk calculator led to an improvement in AUC of less than 0.03 [197]. Based on the available evidence, some biomarkers could help in discriminating between aggressive and non-aggressive tumours with an additional value compared to the prognostic parameters currently used by clinicians [198]. However, upfront multiparametric magnetic resonance imaging (mpMRI) is also likely to affect the utility of above-mentioned biomarkers (see Section 5.2.4). 5.2.3.3 Tests to select men for a repeat biopsy In men with an elevated risk of PCa with a prior negative biopsy, additional information may be gained by the Progensa-PCA3 and SelectMDX DRE urine tests, the serum 4Kscore and PHI tests or a tissue-based epigenetic test (ConfirmMDx). The role of PHI, Progensa PCA3, and SelectMDX in deciding whether to take a repeat biopsy in men who had a previous negative biopsy is uncertain and probably not cost-effective [188]. The ConfirmMDx test is based on the concept that benign prostatic tissue in the vicinity of a PCa focus shows distinct epigenetic alterations. In case PCa is missed at biopsy, demonstration of epigenetic changes in the benign tissue would indicate the presence of carcinoma. The ConfirmMDX test quantifies the methylation level of promoter regions of three genes (Methylated APC, RASSF1 and GSTP1) in benign prostatic tissue. A multi-centre study found a NPV of 88% when methylation was absent in all three markers, implying that a repeat biopsy could be avoided in these men [199]. Given the limited available data and the fact that the role of mpMRI in tumour detection was not accounted for, no recommendation can be made regarding the routine application of ConfirmMDX, in particular in the light of current use of mpMRI before biopsy. Table 5.4 presents an overview of the most commonly available commercial tests. Table 5.4: Description of additional investigational tests after a negative prostate biopsy* Name of test Progensa SelectMDX PHI 4Kscore Test ConfirmMDX

Test substrate DRE urine DRE urine Serum Serum/plasma Benign prostate biopsy

Molecular lncRNA PCA3 mRNA HOXC6, DLX1 Total, free and p2PSA Total, free, intact PSA, hK2 Methylated APC, RASSF1 and GSTP1

FDA approved Yes No Yes No No

*Isolated high-grade prostatic intraepithelial neoplasia (PIN) in one or two biopsy sites is no longer an indication for repeat biopsy [200].

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5.2.3.4

Guidelines for risk-assessment of asymptomatic men

Recommendations In asymptomatic men with a prostate-specific antigen level between 2–10 ng/mL and a normal digital rectal examination, use one oft the following tools for biopsy indication: • risk-calculator; • imaging; • an additional serum, urine or tissue-based test.

Strength rating Strong

Weak

5.2.4 The role of imaging in clinical diagnosis 5.2.4.1 Transrectal ultrasound and ultrasound-based techniques Standard TRUS is not reliable at detecting PCa [201] and the diagnostic yield of additional biopsies performed on hypoechoic lesions is negligible [202]. Prostate HistoScanningTM provided inconsistent results across studies [203]. New sonographic modalities such as micro-Doppler, sonoelastography contrast-enhanced US or high-resolution micro-ultrasound provided promising preliminary findings, either alone, or combined with so-called ‘multiparametric US’. However, these techniques still have limited clinical appllicability due to lack of standardisation, lack of large-scale evaluation of inter-reader variability and unclear results in transition zones [204-206]. 5.2.4.2 Multiparametric magnetic resonance imaging 5.2.4.2.1 Multiparametric magnetic resonance imaging performance in detecting PCa Correlation with RP specimens shows that MRI has good sensitivity for the detection and localisation of ISUP grade > 2 cancers, especially when their diameter is larger than 10 mm [207-209]. This good sensitivity was further confirmed in patients who underwent template biopsies. In a recent Cochrane meta-analysis which compared MRI to template biopsies (> 20 cores) in biopsy-naïve and repeat-biopsy settings, MRI had a pooled sensitivity of 0.91 (95% CI: 0.83–0.95) and a pooled specificity of 0.37 (95% CI: 0.29–0.46) for ISUP grade > 2 cancers [210]. For ISUP grade > 3 cancers, MRI pooled sensitivity and specificity were 0.95 (95% CI: 0.87– 0.99) and 0.35 (95% CI: 0.26–0.46), respectively. MRI is less sensitive in identifying ISUP grade 1 PCa. It identifies less than 30% of ISUP grade 1 cancers smaller than 0.5 cc identified on RP specimens by histopathology analysis [207]. In series using template biopsy findings as the reference standard, MRI has a pooled sensitivity of 0.70 (95% CI: 0.59–0.80) and a pooled specificity of 0.27 (95% CI: 0.19–0.37) for identifying ISUP grade 1 cancers [210]. The probability of detecting malignancy by MRI-identified lesions was standardised first by the use of a 5-grade Likert score [211], and then by the Prostate Imaging – Reporting and Data System (PI-RADS) score which has been updated several times since its introduction [212, 213]. In a meta-analysis of 13 studies involving men with suspected or biopsy-proven PCa, the average PPVs for ISUP grade > 2 cancers of lesions with a PI-RADSv2 score of 3, 4 and 5 were 12%, 48% and 72% respectively, but with significant heterogeneity among studies (Table 5.5) [214]. Another retrospective study of 3,449 men with suspected or biopsy-proven untreated PCa imaged across 26 academic centres found similar results with lesions of PI-RADS v2 scores of 3, 4 and 5 having a PPV for ISUP grade > 2 cancers of 15% (95% CI: 11–19), 39% (95% CI: 34–45) and 72% (95% CI: 61–82), respectively [215]. Table 5.5: Proportion of malignant MRI lesions by ISUP grade groups and PI-RADS v2 scores [214] PI-RADS v2 3 4 5

Total number of lesions 707 886 495

ISUP 1

ISUP 2

ISUP 3

14% (9.4–18.7) 21% (13.0–28.9 12% (5.3–18.7)

9.3% (4.3–14.1) 1.5% (0.05–3) 29.7% (13.9–45.5) 7.7% (3.4–12) 33.5% (8.0–59.0) 15.7% (6.4–25.1)

ISUP > 4 0.7% (0–1.6) 10.8% (5.7–15.9) 23% (8.2–37.9)

Intervals in parenthesis are 95% CIs. 5.2.4.2.2 T  argeted biopsy improves the detection of ISUP grade > 2 cancer as compared to systematic biopsy. In pooled data of 25 reports on agreement analysis (head-to-head comparisons) between systematic biopsy (median number of cores, 8–15) and MRI-targeted biopsies (MRI-TBx; median number of cores, 2–7), the detection ratio (i.e. the ratio of the detection rates obtained by MRI-TBx alone and by systematic biopsy alone) was 1.12 (95% CI: 1.02–1.23) for ISUP grade > 2 cancers and 1.20 (95% CI: 1.06–1.36) for ISUP grade > 3 cancers, and therefore in favour of MRI-TBx.

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However, the pooled detection ratios for ISUP grade > 2 cancers and ISUP grade > 3 cancers were 1.44 (95% CI: 1.19–1.75) and 1.64 (95% CI: 1.27–2.11), respectively, in patients with prior negative systematic biopsies, and only 1.05 (95% CI: 0.95–1.16) and 1.09 (95% CI: 0.94–1.26) in biopsy-naïve patients [210]. Another meta-analysis of RCTs limited to biopsy-naïve patients with a positive MRI found that MRI-TBx detected significantly more ISUP grade > 2 cancers than systematic biopsy (risk difference, -0.11 (95% CI: -0.2 to 0.0); p = 0.05), in prospective cohort studies (risk difference, -0.18 (95% CI: -0.24 to -0.11); p < 0.00001), and in retrospective cohort studies (risk difference, -0.07 (95% CI: -0.12 to -0.02); p = 0.004). There was no significant increase in the detection rate when systematic biopsies were combined to MRI-TBx [216]. Three prospective multi-centre trials evaluated MRI-TBx in biopsy-naïve patients. In the PRostate Evaluation for Clinically Important Disease: Sampling Using Image-guidance Or Not? (PRECISION) trial, 500 biopsy-naïve patients were randomised to either MRI-TBx only or TRUS-guided systematic biopsy only. The detection rate of ISUP grade > 2 cancers was significantly higher in men assigned to MRI-TBx (38%) than in those assigned to SBx (26%, p = 0.005, detection ratio 1.46) [217]. In the Assessment of Prostate MRI Before Prostate Biopsies (MRI-FIRST) trial, 251 biopsy-naïve patients underwent TRUS-guided systematic biopsy by an operator who was blinded to MRI findings, and MRI-TBx by another operator. Magnetic resonance ImagingTBx detected ISUP grade > 2 cancers in a higher percentage of patients but the difference was not significant (32.3% vs. 29.9%, p = 0.38; detection ratio: 1.08) [202]. However, MRI-TBx detected significantly more ISUP grade > 3 cancers than systematic biopsy (19.9% vs. 15.1%, p = 0.0095; detection ratio: 1.32). A similar trend for improved detection of ISUP grade > 3 cancers by MRI-TBx was observed in the Cochrane analysis; however, it was not statistically significant (detection ratio 1.11 [0.88–1.40]) [210]. The Met Prostaat MRI Meer Mans (4M) study included 626 biopsy-naïve patients; all patients underwent systematic biopsy, and those with a positive MRI (PI-RADSv2 score of 3–5, 51%) underwent additional in-bore MRI-TBx. The results were close to those of the MRI-FIRST trial with a detection ratio for ISUP grade > 2 cancers of 1.09 (detection rate: 25% for MRI-TBx vs. 23% for systematic biopsy) [218]. However, in this study, MRI-TBx and systematic biopsy detected an equal number of ISUP grade > 3 cancers (11% vs. 12%; detection ratio: 0.92). The Target Biopsy Techniques Based on Magnetic Resonance Imaging in the Diagnosis of Prostate Cancer in Patients with Prior Negative Biopsies (FUTURE) randomised trial compared three techniques of MRI-TBx in the repeat-biopsy setting [219]. In the subgroup of 152 patients who underwent both MRI-TBx and systematic biopsy, MRI-TBx detected significantly more ISUP grade > 2 cancers than systematic biopsy (34% vs. 16%; p < 0.001, detection ratio of 2.1), which is a finding consistent with the Cochrane agreement analysis (detection ratio: 1.44). An ISUP grade > 2 cancer would have been missed in only 1.3% (2/152) of patients, had systematic biopsy been omitted [220]. These findings support that MRI-TBx significantly out-performs systematic biopsy for the detection of ISUP grade > 2 in the repeat-biopsy setting. In biopsy-naïve patients, the difference appears to be less marked but remains in favour of MRI-TBx. 5.2.4.2.3 M  RI-TBx without systematic biopsy reduces the detection of ISUP grade 1 PCa as compared to systematic biopsy. In pooled data of 25 head-to-head comparisons between systematic biopsy and MRI-TBx, the detection ratio for ISUP grade 1 cancers was 0.62 (95% CI: 0.44–0.88) in patients with prior negative biopsy and 0.63 (95% CI: 0.54–0.74) in biopsy-naïve patients [210]. In the PRECISION and 4M trials, the detection rate of ISUP grade 1 patients was significantly lower in the MRI-TBx group as compared to systematic biopsy (9% vs. 22%, p < 0.001, detection ratio of 0.41 for PRECISION; 14% vs. 25%, p < 0.001, detection ratio of 0.56 for 4M) [217, 218]. In the MRI-FIRST trial, MRI-TBx detected significantly fewer patients with clinically insignificant PCa (defined as ISUP grade 1 and maximum cancer core length < 6 mm) than systematic biopsy (5.6% vs. 19.5%, p < 0.0001, detection ratio of 0.29) [202]. Consequently, MRI-TBx without systematic biopsy significantly reduces over-diagnosis of low-risk disease, as compared to systematic biopsy. 5.2.4.2.4 The added value of systematic and targeted biopsy Magnetic resonance imaging-targeted biopsies can be used in two different diagnostic pathways: 1) the ‘combined pathway’, in which patients with a positive MRI undergo combined systematic and targeted biopsy, and patients with a negative MRI undergo systematic biopsy; 2) the ‘MRI pathway’, in which patients with a positive MRI undergo only MRI-TBx, and patients with a negative MRI who are not biopsied at all. Choosing between these pathways depends not only on the detection rates obtained by the two biopsy techniques, but also on whether or not they detect the same patients. Many studies evaluated combined systematic and targeted biopsy in the same patients and could therefore assess the absolute added value of each technique (i.e. the percentage of patients diagnosed by only one biopsy technique). Data from the Cochrane meta-analysis of these studies and from the MRI-FIRST and 4M trials suggest that the absolute added value of MRI-TBx for detecting ISUP grade > 2 cancers is higher than that of systematic biopsy (see Table 5.6).

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Table 5.6: A  bsolute added values of targeted and systematic biopsies for ISUP grade > 2 and > 3 cancer detection

ISUP grade

Biopsy-naïve

Prior negative biopsy

Added value of MRI-TBx Added value of systematic biopsy Overall prevalence Added value of MRI-TBx Added value of systematic biopsy Overall prevalence

ISUP > 2 Cochrane metaanalysis* [210] 6.3% (4.8-8.2) 4.3% (2.6-6.9)

MRI-FIRST 4M trial trial* [202] [218]

7.6% (4.6-11.6) 5.2% (2.8-8.7)

6.0% (3.4-9.7) 1.2% (0.2-3.5)

27.7% 37.5% (23.7-32.6) (31.4-43.8) 9.6% (7.7-11.8) 2.3% (1.2-4.5) 22.8% (20.0-26.2)

ISUP > 3 Cochrane metaanalysis* [210] 7.0% (ND) 4.7% (3.5-6.3) 5.0% (ND) 2.8% (1.7-4.8)

MRI-FIRST 4M trial trial* [202] [218]

-

30% (ND) 15.5% 21.1% (12.6-19.5) (16.2-26.7) 6.3% (5.2-7.7) 1.1% (0.5-2.6) -

12.6% (10.5-15.6)

-

3.2% (ND) 4.1% (ND)

15% (ND) -

-

*Intervals in parenthesis are 95% CI. The absolute added value of a given biopsy technique is defined by the percentage of patients of the entire cohort diagnosed only by this biopsy technique. ISUP = International Society for Urological Pathology (grade); MRI-TBx = magnetic resonance imaging-targeted biopsies; ND = not defined. In Table 5.6, the absolute added values refer to the percentage of patients in the entire cohort; if the cancer prevalence is taken into account, the ‘relative’ percentage of additional detected PCa can be computed. Adding MRI-TBx to systematic biopsy in biopsy-naïve patients increases the number of ISUP grade > 2 and grade > 3 PCa by approximately 20% and 30%, respectively. In the repeat-biopsy setting, adding MRI-TBx increases detection of ISUP grade > 2 and grade > 3 PCa by approximately 40% and 50%, respectively. Omitting systematic biopsy in biopsy-naïve patients would miss approximately 16% of ISUP grade > 2 PCa and 18% of ISUP grade > 3 PCa. In the repeat-biopsy setting, it would miss approximately 10% of ISUP grade > 2 PCa and 9% of ISUP grade > 3 PCa. 5.2.4.2.5 Number of biopsy procedures potentially avoided in the ‘MR pathway’ The diagnostic yield and number of biopsy procedures potentially avoided by the ‘MR pathway’ depends on the Likert/PI-RADS threshold used to define positive MRI. In pooled studies on biopsy-naïve patients and patients with prior negative biopsies, a Likert/PI-RADS threshold of > 3 would have avoided 30% (95% CI: 23–38) of all biopsy procedures while missing 11% (95% CI: 6–18) of all detected ISUP grade > 2 cancers (relative percentage) [210]. Increasing the threshold to > 4 would have avoided 59% (95% CI: 43–78) of all biopsy procedures while missing 28% (95% CI: 14–48) of all detected ISUP grade > 2 cancers [210]. Of note, the percentages of negative MRI (Likert/PI-RADS score < 2) in the MRI-FIRST, PRECISION and 4M trials were 21.1%, 28.9% and 49%, respectively [202, 217, 218]. 5.2.4.2.6 Other considerations 5.2.4.2.6.1 Multiparametric magnetic resonance imaging reproducibility Despite the use of the PI-RADSv2 scoring system [212], MRI inter-reader reproducibility remains moderate at best which currently limits its broad use by non-dedicated radiologists [221]. However, significant improvement in the accuracy of MRI and MRI-TBx can be observed over time, both in academic and community hospitals, especially after implementation of PI-RADSv2 scoring and multidisciplinary meetings using pathological correlation and feedback [222-225]. An updated version of the PI-RADS score (PI-RADSv2.1) has been recently published to improve reader reproducibility but it has not yet been fully evaluated [213]. It is still too early to predict whether quantitative approaches and computer-aided diagnostic systems will improve the characterisation of lesions seen at MRI [226-228].

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5.2.4.2.6.2 Targeted biopsy accuracy and reproducibility Clinically significant PCa not detected by the ‘MRI pathway’ can be missed because of MRI failure (invisible cancer or reader’s misinterpretation) or because of targeting failure (target missed or undersampled by MRITBx). In two retrospective studies of 211 and 116 patients with a unilateral MRI lesion, targeted biopsy alone detected 73.5–85.5% of all csPCa (ISUP grade > 2); combining MRI-TBx with systematic biopsy of the lobe with the MRI lesion detected 96–96.4% of all csPCas and combined targeted and systematic biopsy of the contralateral lobe only identified 81.6–92.7% of csPCas [229, 230]. The difference may reflect targeting errors leading to undersampling of the tumour. The accuracy of MRI-TBx is indeed substantially impacted by the experience of the biopsy operator [221]. Increasing the number of cores taken per target may partially compensate for guiding imprecision. In a retrospective study of 479 patients who underwent MRI-TBx with 4 cores per target that were sequentially labelled, the first 3 cores detected 95.1% of the csPCas detected by the 4-core strategy [231]. In two other retrospective studies of 330 and 744 patients who underwent MRI-TBx with up to 5 cores per target, the one-core and 3-core sampling strategies detected respectively 63–75% and 90–93% of the ISUP grade > 2 PCa detected by the 5-core strategy [232, 233]. These percentages are likely to be influenced by the lesion size and location, the prostate volume or the operator’s experience, but no study has quantified the impact of these factors yet. 5.2.4.2.6.3 Role of risk-stratification Using risk-stratification to avoid biopsy procedures Prostate-specific antigen density (PSAD) may help refine the risk of csPCa in patients undergoing MRI as PSAD and the PI-RADS score are significant independent predictors of csPCa at biopsy [234, 235]. In a meta-analysis of 8 studies, pooled MRI NPV for ISUP grade > 2 cancer was 84.4% (95% CI: 81.3–87.2) in the wole cohort, 82.7% (95% CI: 80.5–84.7) in biopsy-naïve men and 88.2% (95% CI: 85–91.1) in men with prior negative biopsies. In the subgroup of patients with PSAD < 0.15 ng/ml, NPV increased to respectively 90.4% (95% CI: 86.8–93.4), 88.7% (95% CI: 83.1–93.3) and 94.1% (95% CI: 90.9–96.6) [236]. In contrast, the risk of csPCa is as high as 27–40% in patients with negative MRI and PSAD > 0.15–0.20 ng/mL/cc [218, 235, 237240] (Table 5.7). Combining MRI findings with the PCA3 score may also improve risk stratification [241]. Several groups have developed comprehensive risk calculators which combine MRI findings with simple clinical data as a tool to predict subsequent biopsy results [242]. At external validation, they tended to outperform risk calculators not incorporating MRI findings (ERSPC and PBCG) with good discriminative power (as measured by the AUC). However, they also tended to be miscalibrated with under- or over-prediction of the risk of ISUP grade > 2 cancer [243, 244]. In one study that externally assessed four risk calculators combining MRI findings and clinical data, only two demonstrated a distinct net benefit when a risk of false-negative prediction of 15% was accepted. The others were harmful for this risk level, as compared to the ‘biopsy all’ strategy [243]. This illustrates the prevalence-dependence of risk models. Recalibrations taking into account the local prevalence are possible, but this approach is difficult in routine clinical practice as the local prevalence is difficult to estimate and may change over time. Using risk-stratification to avoid MRI and biopsy procedures A retrospective analysis including 200 men from a prospective database of patients who underwent MRI and combined systematic and targeted biopsy showed that upfront use of the Rotterdam Prostate Cancer Risk Calculator (RPCRC) would have avoided MRI and biopsy in 73 men (37%). Of these 73 men, 10 had ISUP grade 1 cancer and 4 had ISUP grade > 2 cancer [245]. A prospective multi-centre study evaluated several diagnostic pathways in 545 biopsy-naïve men who underwent MRI and systematic and targeted biopsy. Using a PHI threshold of > 30 to perform MRI and biopsy would have avoided MRI and biopsy in 25% of men at the cost of missing 8% of the ISUP grade > 2 cancers [246]. Another prospective multi-centre trial including 532 men (with or without history of prostate biopsy) showed that using a threshold of > 10% for the Stockholm3 test to perform MRI and biopsy would have avoided MRI and biopsy in 38% of men at the cost of missing 8% of ISUP grade > 2 cancers [247].

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Table 5.7: Impact of the PSA density on csPCa detection rates in patients with negative MRI findings Study

Study design

Population

Washino, et al. 2017 [235]

Retrosp. Single-centre

n = 288 Biopsy naive

Distler, et al. 2017 [234]

Hansen, et al. 2017 [237]

Hansen, et al. 2018 [238]

Oishi, et al. 2019 [239]

Boesen, et al. 2019 [240]

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Retrosp. analysis of prospective database Single-centre

Retrosp. Single-centre

Retrosp. Multi-centre

n = 1,040 Biopsy naive + prior negative biopsy

Biopsy protocol csPCa csPCa detection rate definition SBx (14 cores) + ISUP > 2 or Whole cohort (prevalence): cognitive TBx MCCL > 4 mm 49%

TTP (24 cores) + ISUP > 2 fusion TBx

PI-RADS 1-2 / Whole cohort: 11% if PSAD  0.15

TTP (24 cores) + ISUP > 2 n = 514 Prior negative fusion TBx biopsy or AS for ISUP 1 PCa

n = 807 Biopsy naive

PI-RADS 1-2: 0% if PSAD  0.3 Whole cohort (prevalence): 43%

TTP + cognitive or fusion TBx

Retrosp. analysis of prospective database Single-centre

SBx (12 cores) n = 135 Biopsy naive + prior negative biopsy + AS + Restaging Only pts with negative MRI (PI-RADS  2

ISUP > 2

SBx (10 cores) + ISUP > 2 fusion TBx

PI-RADS 1-2 / prior negative biopsy: 7% if PSAD  0.15 Whole cohort (prevalence): 31% Likert 1-2: 9% if PSAD 3), perform targeted biopsy only. When mpMRI is negative (i.e., PI-RADS < 2), and clinical suspicion of PCa is high, perform systematic biopsy based on shared share decision-making with the patient.

Strength rating Strong Weak Strong

5.2.5 Baseline biopsy The need for prostate biopsy is based on PSA level, other biomarkers and/or suspicious DRE and/or imaging (see Section 5.2.4). Age, potential co-morbidity and therapeutic consequences should also be considered and discussed beforehand [253]. Risk stratification is a potential tool for reducing unnecessary biopsies [253]. Limited PSA elevation alone should not prompt immediate biopsy. Prostate-specific antigen level should be verified after a few weeks, in the same laboratory using the same assay under standardised conditions (i.e. no ejaculation, manipulations, and urinary tract infections [UTIs]) [254, 255]. Empiric use of antibiotics in an asymptomatic patient in order to lower the PSA should not be undertaken [256]. Ultrasound (US)-guided biopsy is now the standard of care. Prostate biopsy is performed by either the transrectal or transperineal approach. Cancer detection rates, when performed without prior imaging with MRI, are comparable between the two approaches [257], however, some evidence suggests reduced infection risk with the transperineal route (see Section 5.2.6.4) [258, 259]. Transurethral resection of the prostate (TURP) should not be used as a tool for cancer detection [260]. 5.2.6 Repeat biopsy 5.2.6.1 Repeat biopsy after previously negative biopsy The indications for repeat biopsy are: • rising and/or persistently elevated PSA (see Table 5.3 for risk estimates); • suspicious DRE, 5–30% PCa risk [153, 154]; • intraductal carcinoma as a solitary finding, > 90% risk of associated high-grade PCa [261]; • positive mpMRI findings (see Section 5.2.4.2). The recommendation to perform a repeat biopsy after a diagnosis of atypical small acinar proliferation and extensive high-grade PIN is based on earlier studies on systematic biopsies using a 6–10 core biopsy protocol. In a contemporary series of biopsies the likelihood of finding a csPCa after follow-up biopsy after a diagnosis of atypical small acinar proliferation was only 6% [262]. The added value of other biomarkers remains unclear (see Sections 5.2.3.1 and 5.2.3.2). 5.2.6.2 Saturation biopsy The incidence of PCa detected by saturation repeat biopsy (> 20 cores) is 30–43% and depends on the number of cores sampled during earlier biopsies [263]. Saturation biopsy may be performed with the transperineal technique, which detects an additional 38% of PCa. The rate of urinary retention varies substantially from 1.2% to 10% [264-267]. 5.2.7 Prostate biopsy procedure 5.2.7.1 Sampling sites and number of cores On baseline biopsies, where no prior imaging with mpMRI has been performed, or where mpMRI has not shown any suspicious lesion, the sample sites should be bilateral from apex to base, as far posterior and lateral as possible in the peripheral gland. Additional cores should be obtained from suspect areas identified by DRE; suspect areas on TRUS might be consideration for additional biopsies. Sextant biopsy is no longer considered adequate. At least 8 systematic biopsies are recommended in prostates with a size of about 30 cc [268]. Ten to

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12 core biopsies are recommended in larger prostates, with > 12 cores not being significantly more conclusive [269, 270]. Eighteen to 24 template cores may be taken in transperineal biopsy with acceptable morbidity, but it is unknown whether this number improves detection of significant cancer [271-273]. As per transrectal biopsy, for maximal detection of significant cancer, cores should be directed towards the peripheral zone posteriorly and laterally, but in transperineal biopsy can also more easily be directed to the anterior horns of the peripheral zone as well. In the setting of a positive MRI with targeted biopsy cores being taken, the addition of template cores may increase the detection of significant cancer slightly, but also increases the detection of insignificant cancer [274, 275]. The optimal number of template cores in this setting is unknown. Where mpMRI has shown a suspicious lesion MR-TBx can be obtained through cognitive guidance, US/MR fusion software or direct in-bore guidance. Current literature, including systematic reviews and meta-analyses, does not show a clear superiority of one image-guided technique over another [219, 276-279]. However, regarding approach, the only systematic review and meta-analysis comparing MRI-targeted transrectal biopsy to MRI-targeted transperineal biopsy, analysing 8 studies, showed a higher sensitivity for detection of csPCa when the transperineal approach was used (86% vs. 73%) [280]. This benefit was especially pronounced for anterior tumours. Multiple (3–5) cores should be taken from each lesion (see Section 5.2.4.2.7.2). 5.2.7.2 Antibiotics prior to biopsy 5.2.7.2.1 Transperineal prostate biopsy A total of seven randomised studies including 1,330 patients compared the impact of biopsy route on infectious complications. Infectious complications were significantly higher following transrectal biopsy (37 events among 657 men) compared to transperineal biopsy (22 events among 673 men) (RR: 1.81 [range 1.09–3.00], 95% CI) [281-288]. In addition, a systematic review including 165 studies with 162,577 patients described sepsis rates of 0.1% and 0.9% for transperineal and transrectal biopsies, respectively [289]. Finally, a population-based study from the UK (n = 73,630) showed lower re-admission rates for sepsis in patients who had transperineal vs. transrectal biopsies (1.0% vs. 1.4%, respectively) [290]. The available evidence demonstrates that the transrectal approach should be abandoned in favour of the transperineal approach despite any possible logistical challenges. To date, no RCT has been published investigating different antibiotic prophylaxis regimens for transperineal prostate biopsy. However, as it is a clean procedure that avoids rectal flora, quinolones or other antibiotics to cover rectal flora may not be necessary. A single dose of cephalosporin only to cover skin commensals has been shown to be sufficient in multiple single cohort series [267, 291]. Prior negative mid-stream urine (MSU) test and routine surgical disinfecting preparation of the perineal skin are mandatory. In one of the largest studies to date, 1,287 patients underwent transperineal biopsy under local anaesthesia only [292]. Antibiotic prophylaxis consisted of a single oral dose of either cefuroxime or cephalexin. Patients with cardiac valve replacements received amoxycillin and gentamicin, and those with severe penicillin allergy received sulphamethoxazole. No quinolones were used. Only one patient developed a UTI with positive urine culture and there was no urosepsis requiring hospitalisation. In another study of 577 consecutive patients undergoing transperineal biopsy using single dose IV cephazolin prophylaxis, one patient (0.2%) suffered prostatitis not requiring hospitalisation [267]. There were no incidences of sepsis. In a further study of 485 patients using only cephazolin, 4 patients (0.8%) suffered infectious complications [293]. 5.2.7.2.2 Transrectal prostate biopsy Meta-analysis of eight RCTs including 1,786 men showed that use of a rectal povidone-iodine preparation before biopsy, in addition to antimicrobial prophylaxis, resulted in a significantly lower rate of infectious complications (RR [95% CIs] 0.55 [0.41–0.72]) [288, 294-299]. Single RCTs showed no evidence of benefit for perineal skin disinfection [300], but reported an advantage for rectal povidone-iodine preparation before biopsy compared to after biopsy [301]. A meta-analysis of four RCTs including 671 men evaluated the use of rectal preparation by enema before transrectal biopsy. No significant advantage was found regarding infectious complications (RR [95% CIs] 0.96 [0.64–1.54]) [288, 302-304]. A meta-analysis of 26 RCTs with 3,857 patients found no evidence that use of peri-prostatic injection of local anaesthesia resulted in more infectious complications than no injection (RR [95% CIs] 1.07 [0.77-1.48]) [288]. A meta-analysis of 9 RCTs including 2,230 patients found that extended biopsy templates showed comparable infectious complications to standard templates (RR [95% CIs] 0.80 [0.53-1.22]) [288]. Additional meta-analyses found no difference in infections complications regarding needle guide type (disposable vs. reusable), needle type (coaxial vs. non-coaxial), needle size (large vs. small), and number of injections for peri-prostatic nerve block (standard vs. extended) [288]. PROSTATE CANCER - LIMITED UPDATE 2021

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A meta-analysis of eleven studies with 1,753 patients showed significantly reduced infections after transrectal prostate biopsy when using antimicrobial prophylaxis as compared to placebo/control (RR [95% CI] 0.56 [0.40– 0.77]) [305]. Fluoroquinolones have been traditionally used for antibiotic prophylaxis in this setting; however, overuse and misuse of fluoroquinolones has resulted in an increase in fluoroquinolone resistance. In addition, the European Commission has implemented stringent regulatory conditions regarding the use of fluoroquinolones resulting in the suspension of the indication for peri-operative antibiotic prophylaxis including prostate biopsy [306]. A systematic review and meta-analysis on antibiotic prophylaxis for the prevention of infectious complications following prostate biopsy concluded that in countries where fluoroquinolones are allowed as antibiotic prophylaxis, a minimum of a full one-day administration, as well as targeted therapy in case of fluoroquinolone resistance, or augmented prophylaxis (combination of two or more different classes of antibiotics) is recommended [305]. In countries where use of fluoroquinolones are suspended, cephalosporins or aminoglycosides can be used as individual agents with comparable infectious complications based on a meta-analysis of two RCTs [305]. A meta-analysis of three RCTs reported that fosfomycin trometamol was superior to fluoroquinolones (RR [95% CI] 0.49 [0.27–0.87]) [305], but routine general use should be critically assessed due to the relevant infectious complications reported in non-randomised studies [307]. Another possibility is the use of augmented prophylaxis without fluoroquinolones, although no standard combination has been established to date. Finally, targeted prophylaxis based on rectal swap/stool culture is plausible, but no RCTs are available on non-fluoroquinolones. See figure 5.1 for prostate biopsy workflow to reduce infections complications. Based on a meta-analysis, suggested antimicrobial prophylaxis before transrectal biopsy may consist of: 1. Targeted prophylaxis - based on rectal swab or stool culture. 2. Augmented prophylaxis - two or more different classes of antibiotics (of note: this option is against antibiotic stewardship programmes). 3. Alternative antibiotics: • fosfomycin trometamol (e.g., 3 g before and 3 g 24–48 hrs. after biopsy); • cephalosporin (e.g., ceftriaxone 1 g i.m; cefixime 400 mg p.o for 3 days starting 24 hrs. before biopsy) aminoglycoside (e.g., gentamicin 3 mg/kg i.v.; amikacin 15 mg/kg i.m). 5.2.7.3

Summary of evidence and recommendations for performing prostate biopsy (in line with the Urological Infections Guidelines Panel)

Summary of evidence A meta-analysis of seven studies including 1,330 patients showed significantly reduced infectious complications in patients undergoing transperineal biopsy as compared to transrectal biopsy. Meta-analysis of eight RCTs including 1,786 men showed that use of a rectal povidone-iodine preparation before transrectal biopsy, in addition to antimicrobial prophylaxis, resulted in a significantly lower rate of infectious complications. A meta-analysis on eleven studies with 1,753 patients showed significantly reduced infections after transrectal biopsy when using antimicrobial prophylaxis as compared to placebo/control.

Recommendations Perform prostate biopsy using the transperineal approach due to the lower risk of infectious complications. Use routine surgical disinfection of the perineal skin for transperineal biopsy. Use rectal cleansing with povidone-iodine in men prior to transrectal prostate biopsy. Do not use fluoroquinolones for prostate biopsy in line with the European Commission final decision on EMEA/H/A-31/1452. Use either target prophylaxis based on rectal swab or stool culture; augmented prophylaxis (two or more different classes of antibiotics); or alternative antibiotics (e.g., fosfomycin trometamol, cephalosporin, aminoglycoside) for antibiotic prophylaxis for transrectal biopsy. Use a single oral dose of either cefuroxime or cephalexin or cephazolin as antibiotic prophylaxis for transperineal biopsy. Patients with severe penicillin allergy may be given sulphamethoxazole. Ensure that prostate core biopsies from different sites are submitted separately for processing and pathology reporting.

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LE 1a 1a

1a

Strength rating* Strong Strong Strong Strong Weak

Weak

Strong

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Figure 5.1: Prostate biopsy workflow to reduce infectious complications*

Indication for prostate biopsy?

Transperineal biopsy feasible? Yes

No

Transperineal biopsy - 1st choice (⊕⊕⊝⊝) with: • perineal cleansing • antibiotic prophylaxis

Transrectal biopsy – 2nd choice (⊕⊕⊝⊝)

with: • povidone-iodine rectal preparation • antibiotic prophylaxis

Fluoroquinolones licensed?

Yes

No 1.

Targeted prophylaxis: based on rectal swab or stool cultures

2.

Augmented prophylaxis: two or more different classes of antibiotics

3.

Alternative antibiotics (⊕⊝⊝⊝):

• fosfomycin trometamol (e.g. 3 g before and 3 g 24-48 hrs after biopsy) • cephalosporin (e.g. ceftriaxone 1 g i.m.; cefixime 400 mg p.o. for 3 days starting 24 hrs before biopsy) • aminoglycoside (e.g. gentamicin 3 mg/kg i.v.; amikacin 15 mg/kg i.m.)

Duration of antibiotic prophylaxis ≥ 24 hrs (⊕⊕⊝⊝) 1.

Targeted prophylaxis (⊕⊕⊝⊝): based on rectal swab or stool cultures

2.

Augmented prophylaxis (⊕⊝⊝⊝):

3.

• Fluoroquinolone plus aminoglycoside • Fluoroquinolone plus cephalosporin

Fluoroquinolone prophylaxis

(range: ⊕⊝⊝⊝ - ⊕⊕⊝⊝)

GRADE Working Group grades of evidence. • High certainty: (⊕⊕⊕⊕) very confident that the true effect lies close to that of the estimate of the effect. • M  oderate certainty: (⊕⊕⊕) moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. • L  ow certainty: (⊕⊕) confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. • V  ery low certainty: (⊕) very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. *Figure adapted from Pilatz et al., [308] with permission from Elsevier. *Note on strength ratings: The above strength ratings are explained here due to the major clinical implications of these new recommendations. Although data showing the lower risk of infection via the transperineal approach is low in certainty, its statistical and clinical significance warrants its Strong rating. Strong ratings are also given for routine surgical disinfection of skin in transperineal biopsy and povidone-iodine rectal cleansing in transrectal biopsy as, although quality of data is low, the clinical benefit is high and practical application simple. A ‘Strong’ rating is given for avoiding fluoroquinolones in prostate biopsy due to its legal implications in Europe. 5.2.7.4 Local anaesthesia prior to biopsy Ultrasound-guided peri-prostatic block is recommended [309]. It is not important whether the depot is apical or basal. Intra-rectal instillation of local anaesthesia is inferior to peri-prostatic infiltration [310]. Local anaesthesia can also be used effectively for mpMRI-targeted and systemic transperineal biopsy [311]. Patients are placed in the lithotomy position. Bupivacaine is injected into the perineal skin and subcutaneous tissues, followed two minutes later by a peri-prostatic block. A systematic review evaluating pain in 3 studies comparing transperineal vs. transrectal biopsies found that the transperineal approach significantly increased patient pain

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(RR: 1.83 [1.27–2.65]) [312]. In a randomised comparison a combination of peri-prostatic and pudendal block anaesthesia reduced pain during transperineal biopsies compared to peri-prostatic anaesthesia only [313]. Targeted biopsies can then be taken via a brachytherapy grid or a freehand needle-guiding device under local infiltration anaesthesia [311, 314, 315]. 5.2.7.5 Complications Complications of TRUS biopsy are listed in Table 5.8 [316]. Mortality after prostate biopsy is extremely rare and most are consequences of sepsis [111]. Low-dose aspirin is no longer an absolute contraindication [317]. A systematic review found favourable infection rates for transperineal compared to TRUS biopsies with similar rates of haematuria, haematospermia and urinary retention [318]. A meta-analysis of 4,280 men randomised between transperineal vs. TRUS biopsies in 13 studies found no significant differences in complication rates, however, data on sepsis compared only 497 men undergoing TRUS biopsy to 474 having transperineal biopsy. The transperineal approach required more (local) anaesthesia [257]. Table 5.8: Percentage of complications per TRUS biopsy session, irrespective of the number of cores Complications Haematospermia Haematuria > 1 day Rectal bleeding  38.5°C Epididymitis Rectal bleeding > 2 days +/− surgical intervention Urinary retention Other complications requiring hospitalisation

Percentage of patients affected 37.4 14.5 2.2 1.0 0.8 0.7 0.7 0.2 0.3

5.2.7.6 Seminal vesicle biopsy Indications for seminal vesicle (SV) (staging) biopsies are poorly defined. At a PSA of > 15 ng/mL, the odds of tumour involvement are 20–25% [319]. A SV staging biopsy is only useful if it has a decisive impact on treatment, such as ruling out radical tumour resection or for potential subsequent RT. Its added value compared with mpMRI is questionable. 5.2.7.7 Transition zone biopsy Transition zone sampling during baseline biopsies has a low detection rate and should be limited to MRIdetected lesions or repeat biopsies [320]. 5.2.8 Pathology of prostate needle biopsies 5.2.8.1 Processing Prostate core biopsies from different sites are processed separately. Before processing, the number and length of the cores are recorded. The length of biopsy tissue significantly correlates with the PCa detection rate [321]. To achieve optimal flattening and alignment, a maximum of three cores should be embedded per tissue cassette, and sponges or paper used to keep the cores stretched and flat [322, 323]. To optimise detection of small lesions, paraffin blocks should be cut at three levels and intervening unstained sections may be kept for immunohistochemistry (IHC) [320]. 5.2.8.2 Microscopy and reporting Diagnosis of PCa is based on histology. The diagnostic criteria include features pathognomonic of cancer, major and minor features favouring cancer and features against cancer. Ancillary staining and additional (deeper) sections should be considered if a suspect lesion is identified [324-326]. Diagnostic uncertainty is resolved by intradepartmental or external consultation [324]. Section 5.2.8.3 lists the recommended terminology for reporting prostate biopsies [322]. Type and subtype of PCa should be reported such as for instance acinar adenocarcinoma (> 95% of PCa), ductal adenocarcinoma (< 5%) and poorly differentiated small or large cell neuroendocrine carcinoma (< 1%), even if representing a small proportion of the PCa. The distinct aggressive nature of ductal adenocarcinoma and small/large cell neuroendocrine carcinoma should be commented upon in the pathology report [322].

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5.2.8.2.1 Recommended terminology for reporting prostate biopsies [255] Recommendations Benign/negative for malignancy; if appropriate, include a description. Active inflammation. Granulomatous inflammation. High-grade prostatic intraepithelial neoplasia (PIN). High-grade PIN with atypical glands, suspicious for adenocarcinoma (PINATYP). Focus of atypical glands/lesion suspicious for adenocarcinoma/atypical small acinar proliferation, suspicious for cancer. Adenocarcinoma, provide type and subtype. Intraductal carcinoma.

Strength rating Strong

Each biopsy site should be reported individually, including its location (in accordance with the sampling site) and histopathological findings, which include the histological type and the ISUP 2014 grade [84]. For mpMRI targeted biopsies consisting of multiple cores per target the aggregated ISUP grade and percentage of highgrade carcinoma should be reported per targeted lesion [85]. If the targeted biopsies are negative, presence of specific benign pathology should be mentioned, such as dense inflammation, fibromuscular hyperplasia or granulomatous inflammation [327]. A global ISUP grade comprising all systematic (non-targeted) biopsies is also reported (see Section 4.2). The global ISUP grade takes into account all systemic biopsies positive for carcinoma, by estimating the total extent of each Gleason grade present. For instance, if three biopsy sites are entirely composed of Gleason grade 3 and one biopsy site of Gleason grade 4 only, the global ISUP grade would be 2 (i.e. GS 7[3+4]) or 3 (i.e. GS 7[4+3]), dependent on whether the extent of Gleason grade 3 exceeds that of Gleason grade 4, whereas the worse grade would be ISUP grade 4 (i.e. GS 8[4+4]). Recent publications demonstrated that global ISUP grade is somewhat superior in predicting prostatectomy ISUP grade [328] and BCR [329]. Lymphovascular invasion (LVI) and extraprostatic extension (EPE) must each be reported, if identified. More recently, expansile cribriform pattern of PCa as well as intraductal carcinoma in biopsies were identified as independent prognosticators of metastatic disease [330] and PCa-specific survival [331] and presence of both adverse pathologies should be reported [85]. The proportion of systematic (non-targeted) carcinoma-positive cores as well as the extent of tumour involvement per biopsy core correlate with the ISUP grade, tumour volume, surgical margins and pathologic stage in RP specimens and predict BCR, post-prostatectomy progression and RT failure. These parameters are included in nomograms created to predict pathologic stage and SV invasion after RP and RT failure [332-334]. A pathology report should therefore provide both the proportion of carcinoma-positive cores and the extent of cancer involvement for each core. The length in mm and percentage of carcinoma in the biopsy have equal prognostic impact [335]. An extent of > 50% of adenocarcinoma in a single core is used in some AS protocols as a cut off [336] triggering immediate treatment vs. AS in patients with ISUP grade 1. A prostate biopsy that does not contain glandular tissue should be reported as diagnostically inadequate. Mandatory elements to be reported for a carcinoma-positive prostate biopsy are: • type of carcinoma; • primary and secondary/worst Gleason grade (per biopsy site and global); • percentage high-grade carcinoma (global); • extent of carcinoma (in mm or percentage) (per biopsy site); • if present: EPE, SV invasion, LVI, intraductal carcinoma/cribriform pattern, peri-neural invasion; • ISUP grade (global); • In targeted biopsies aggregate ISUP grade and percentage high-grade carcinoma per targeted site; • In carcinoma-negative targeted biopsy report specific benign pathology, e.g., fibromuscular hyperplasia or granulomatous inflammation, if present [85]; 5.2.8.3 Tissue-based prognostic biomarker testing After a comprehensive literature review and several panel discussions an ASCO-EAU-AUA multidisciplinary expert panel made recommendations regarding the use of tissue-based PCa biomarkers. The recommendations were limited to 5 commercially available tests (Oncotype Dx®, Prolaris®, Decipher®, Decipher PORTOS and ProMark®) with extensive validation in large retrospective studies and evidence that their test results might actually impact clinical decision-taking [337].

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The selected commercially available tests significantly improved the prognostic accuracy of clinical multivariable models for identifying men who would benefit of AS and those with csPCa requiring curative treatment, as well as for guidance of patient management after RP. In addition, a few studies showed that tissue biomarker tests and MRI findings independently improved the detection of clinically significant cancer in an AS setting, but it remains unclear which men would benefit of both tests. Since the long-term impact of the use of these commercially available tests on oncological outcome remains unproven and prospective trials are largely lacking, the Panel concluded that these tests should not be offered routinely but only in subsets of patients where the test result provides clinically actionable information, such as for instance in men with favourable intermediate-risk PCa who might opt for AS or men with unfavourable intermediate-risk PCa scheduled for RT to decide on treatment intensification with hormonal therapy (HT). 5.2.8.4 Histopathology of radical prostatectomy specimens 5.2.8.4.1 Processing of radical prostatectomy specimens Histopathological examination of RP specimens describes the pathological stage, histopathological type, grade and surgical margins of PCa. It is recommended that RP specimens are totally embedded to enable assessment of cancer location, multifocality and heterogeneity. For cost-effectiveness, partial embedding may also be considered, particularly for prostates > 60 g. The most widely accepted method includes complete embedding of the posterior prostate and a single mid-anterior left and right section. Compared with total embedding, partial embedding detected 98% of PCa with an ISUP grade > 2 with accurate staging in 96% of cases [338]. The entire RP specimen should be inked upon receipt in the laboratory to demonstrate the surgical margins. Specimens are fixed by immersion in buffered formalin for at least 24 hours, preferably before slicing. Fixation can be enhanced by injecting formalin which provides more homogeneous fixation and sectioning after 24 hours [339]. After fixation, the apex and the base (bladder neck) are removed and cut into (para)sagittal or radial sections; the shave method is not recommended [83]. The remainder of the specimen is cut in transverse, 3–4 mm sections, perpendicular to the long axis of the urethra. The resultant tissue slices can be embedded and processed as whole-mounts or after quadrant sectioning. Whole-mounts provide better topographic visualisation, faster histopathological examination and better correlation with pre-operative imaging, although they are more time-consuming and require specialist handling. For routine sectioning, the advantages of whole mounts do not outweigh their disadvantages. 5.2.8.4.1.1 Guidelines for processing prostatectomy specimens Recommendations Ensure total embedding, by conventional (quadrant) or whole-mount sectioning. Ink the entire surface before cutting, to evaluate the surgical margin. Examine the apex and base separately, using the cone method with sagittal or radial sectioning.

Strength rating Strong Strong Strong

5.2.8.4.2 Radical prostatectomy specimen report The pathology report provides essential information on the prognostic characteristics relevant for clinical decision-making (Table 5.9). As a result of the complex information to be provided for each RP specimen, the use of synoptic(-like) or checklist reporting is recommended (Table 5.10). Synoptic reporting results in more transparent and complete pathology reporting [340]. Table 5.9: Mandatory elements provided by the pathology report Histopathological type: > 95% of PCa represents conventional (acinar) adenocarcinoma. Grading according to ISUP grade (or not applicable if therapy-related changes). Presence of intraductal and/or cribriform carcinoma. Tumour (sub)staging and surgical margin status: location and extent of EPE, presence of bladder neck invasion, laterality of EPE or SV invasion, location and extent of positive surgical margins. Additional information may be provided on multifocality, and diameter/volume and zonal location of the dominant tumour.

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Table 5.10: Example checklist: reporting of prostatectomy specimens Histopathological type Type of carcinoma, e.g. conventional acinar, or ductal Histological grade Primary (predominant) Gleason grade Secondary Gleason grade Tertiary Gleason grade (if applicable) Global ISUP grade Approximate percentage of Gleason grade 4 or 5 Tumour quantitation (optional) Percentage of prostate involved Size/volume of dominant tumour nodule Pathological staging (pTNM) If extraprostatic extension is present: • indicate whether it is focal or extensive*; • specify sites; • indicate whether there is seminal vesicle invasion. If applicable, regional lymph nodes: • location; • number of nodes retrieved; • number of nodes involved. Surgical margins If carcinoma is present at the margin: • specify sites. Other Presence of lymphovascular/angio-invasion Location of dominant tumour Presence of intraductal carcinoma/cribriform architecture *Focal is defined as carcinoma glands extending less than 1 high-power field (HPF) in the extraprostatic fat in 1 or 2 sections and extensive is extension beyond or in more sections.

5.2.8.4.3 ISUP grade in prostatectomy specimens Grading of conventional prostatic adenocarcinoma using the (ISUP 2014 modified) Gleason system is the strongest prognostic factor for clinical behaviour and treatment response [84]. The ISUP grade is incorporated in nomograms that predict disease-specific survival (DSS) after prostatectomy [341]. The ISUP grade is based on the sum of the most and second-most dominant (in terms of volume) Gleason grade. ISUP grade 1 is GS 6. ISUP grades 2 and 3 represent carcinomas constituted of Gleason grade 3 and 4 components, with ISUP grade 2 when 50% of the carcinoma, or more, is Gleason grade 3 and ISUP grade 3 when the grade 4 component represents more than 50% of the carcinoma. In a carcinoma almost entirely composed of Gleason grade 3 the presence of a minor (< 5%) Gleason pattern 4 component is not included in the Gleason score (ISUP grade 1), but its presence is commented upon. ISUP grade 4 is largely composed of Gleason grade 4 and ISUP grade 5 of a combination of Gleason grade 4 and 5 or only Gleason grade 5. A global ISUP grade is given for multiple tumours, but a separate tumour focus with a higher ISUP grade should also be mentioned. Tertiary Gleason grade 5, if > 5% of the PCa volume, is an unfavourable prognostic indicator for BCR and should be incorporated in the ISUP grade. If less than 5% its presence should be mentioned in the report [85, 342]. 5.2.8.4.4 Definition of extraprostatic extension Extraprostatic extension is defined as carcinoma mixed with peri-prostatic adipose tissue, or tissue that extends beyond the prostate gland boundaries (e.g., neurovascular bundle, anterior prostate). Microscopic bladder neck invasion is considered EPE. It is useful to report the location and extent of EPE because the latter is related to recurrence risk [343]. There are no internationally accepted definitions of focal or microscopic, vs. non-focal or extensive EPE. Some describe focal as a few glands [344] or < 1 HPF in one or at most two sections [345] whereas others measure the depth of extent in millimetres [346].

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At the apex of the prostate, tumour mixed with skeletal muscle does not constitute EPE. In the bladder neck, microscopic invasion of smooth muscle fibres is not equated to bladder wall invasion, i.e. not as pT4, because it does not carry independent prognostic significance for PCa recurrence and should be recorded as EPE (pT3a) [347, 348]. Stage pT4 is only assigned when the tumour invades the bladder muscle wall as determined macroscopically [349]. 5.2.8.4.5 PCa volume The independent prognostic value of PCa volume in RP specimens has not been established [345, 350-353]. Nevertheless, a cut-off of 0.5 mL is traditionally used to distinguish insignificant from clinically relevant cancer [350]. Improvement in prostatic radio-imaging allows more accurate pre-operative measurement of cancer volume. It is recommended that at least the diameter/volume of the dominant tumour nodule should be assessed, or a rough estimate of the percentage of cancer tissue provided [354]. 5.2.8.4.6 Surgical margin status Surgical margin is an independent risk factor for BCR. Margin status is positive if tumour cells are in contact with the ink on the specimen surface. Margin status is negative if tumour cells are close to the inked surface [351] or at the surface of the tissue lacking ink. In tissues that have severe crush artefacts, it may not be possible to determine margin status [355]. Surgical margin is separate from pathological stage, and a positive margin is not evidence of EPE [356]. There is insufficient evidence to prove a relationship between margin extent and recurrence risk [345]. However, some indication must be given of the multifocality and extent of margin positivity, such as the linear extent in mm of involvement: focal, < 1 mm vs. extensive, > 1 mm [357], or number of blocks with positive margin involvement. Gleason score at the positive margin was found to correlate with outcome, and should be reported [313].

5.3

Diagnosis - Clinical Staging

5.3.1 T-staging The cT category used in the risk table only refers to the DRE finding. The imaging parameters and biopsy results for local staging are, so far, not part of the risk category stratification [358]. 5.3.1.1 TRUS Transrectal ultrasound is no more accurate at predicting organ-confined disease than DRE [359]. Some singlecentre studies reported good results in local staging using 3D TRUS or colour Doppler but these good results were not confirmed by large-scale studies [360, 361]. 5.3.1.2 MRI T2-weighted imaging remains the most useful method for local staging on MRI. At 1.5 Tesla, MRI has good specificity but low sensitivity for detecting T3 stages. Pooled data from a meta-analysis showed a sensitivity and specificity of 0.57 (95% CI: 0.49–0.64) and 0.91 (95% CI: 0.88–0.93), 0.58 (95% CI: 0.47–0.68) and 0.96 (95% CI: 0.95–0.97), and 0.61 (95% CI: 0.54–0.67) and 0.88 (95% CI: 0.85–0.91), for EPE, SVI, and overall stage T3 assessement, respectively [362]. Magnetic resonance imaging cannot detect microscopic EPE. Its sensitivity increases with the radius of extension within peri-prostatic fat. In one study, the EPE detection rate increased from 14 to 100% when the radius of extension increased from < 1 mm to > 3 mm [363]. In another study, MRI sensitivity, specificity and accuracy for detecting pT3 stage were 40%, 95% and 76%, respectively, for focal (i.e. microscopic) EPE, and 62%, 95% and 88% for extensive EPE [364]. The use of high field strength (3 Tesla) or functional imaging in addition to T2-weighted imaging improves sensitivity for EPE or SVI detection [362] but the experience of the reader remains of paramount importance [365] and the inter-reader agreement remains moderate with kappa values ranging from 0.41 to 0.68 [366]. Several series suggested that MRI findings could improve the prediction of the pathological stage when combined with clinical and biopsy data [248]. However, all these studies were based on cohorts of men diagnosed with systematic biopsy and their generalisability in the targeted biopsy setting is questionable. For risk calculators predicting EPE and SVI based on MRI findings, clinical data and combined systematic and targeted biopsy results have been recently reported [367], but they have not undergone external validation yet. Given its low sensitivity for focal (microscopic) EPE, MRI is not recommended for local staging in low-risk patients [368-370]. However, MRI can still be useful for treatment planning.

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5.3.2 N-staging 5.3.2.1 Computed tomography and magnetic resonance imaging Abdominal CT and T1-T2-weighted MRI indirectly assess nodal invasion by using LN diameter and morphology. However, the size of non-metastatic LNs varies widely and may overlap the size of LN metastases. Usually, LNs with a short axis > 8 mm in the pelvis and > 10 mm outside the pelvis are considered malignant. Decreasing these thresholds improves sensitivity but decreases specificity. As a result, the ideal size threshold remains unclear [371, 372]. Computed tomography (CT) and MRI sensitivity is less than 40% [373, 374]. Among 4,264 patients, 654 (15.3%) of whom had positive LNs at LND, CT was positive in only 105 patients (2.5%) [371]. In a multi-centre database of 1,091 patients who underwent pelvic LN dissection, CT sensitivity and specificity were 8.8% and 98%, respectively [375]. Detection of microscopic LN invasion by CT is < 1% in patients with ISUP grade < 4 cancer, PSA < 20 ng/mL, or localised disease [376-378]. Diffusion-weighted MRI (DW-MRI) may detect metastases in normal-sized nodes, but a negative DW-MRI cannot rule out the presence of LN metastases [372, 379]. 5.3.2.2 Risk calculators incorporating MRI findings Because CT and MRI lack sensitivity for direct detection of positive LNs, nomograms combining clinical and biopsy findings (such as the nomograms developed by the Memorial Sloan Cancer Center (MSKCC) [380], by Briganti et al. or by Gandaglia et al. [381, 382] have been used to identify patients at higher risk of LN invasion who should be considered for LN dissection. Although these nomograms are associated with good performance, they have been developed using systematic biopsy findings and may therefore not be sensitive to patients diagnosed with combined MRI-TBx and systematic biopsy. Two models incorporating MRI-TBx biopsy findings and MRI-derived findings recently underwent external validation [367, 383]. One model tested on an external cohort of 187 patients treated by RP and extended LN dissection showed a prevalence of LN invasion of 13.9% (vs. 16.9% in the development cohort). The C-index was 0.73 (vs. 0.81 in the development cohort); at calibration analysis, the model tended to overpredict the actual risk [383]. Another model was validated in an external multi-centre cohort of 487 patients with a prevalence of 8% of LN invasion (vs. 12.5% in the development cohort).The AUC was 0.79 (vs. 0.81 in the development cohort). Using a risk cut-off of 7% would have avoided LN dissection in 56% of patients, while missing LN invasion in 13 (34%) of the 38 patients with LN invasion [367]. 5.3.2.3 Choline PET/CT In a meta-analysis of 609 patients, pooled sensitivity and specificity of choline PET/CT for pelvic LN metastases were 62% (95% CI: 51–66%) and 92% (95% CI: 89–94%), respectively [384]. In a prospective trial of 75 patients at intermediate risk of nodal involvement (10–35%), the sensitivity was only 8.2% at region-based analysis and 18.9% at patient-based analysis, which is too low to be of clinical value [385]. The sensitivity of choline PET/CT increases to 50% in patients at high risk and to 71% in patients at very high risk, in both cases out-performing contrast-enhanced CT [386]. However, comparisons between choline PET/CT and DW-MRI yielded contradictory results, with PET/CT sensitivity found to be superior [387], similar [388, 389] or inferior [385] than that of DW-MRI. Due of its low sensitivity, choline PET/CT does not reach clinically acceptable diagnostic accuracy for detection of LN metastases, or to rule out a nodal dissection based on risk factors or nomograms (see Section 6.3.4.1.2). 5.3.2.4 Prostate-specific membrane antigen-based PET/CT Prostate-specific membrane antigen (PSMA) positron-emission tomography (PET)/CT uses several different radiopharmaceuticals; the majority of published studies used 68Ga-labelling for PSMA PET imaging, but some used 18F-labelling. At present there are no conclusive data about comparison of such tracers, with additional new radiotracers being developed. 68Ga-labelled or 18F-labelled radiotracers for PSMA PET/CT imaging provide good contrast-to-noise ratio, thereby improving the detectability of lesions. Prostate-specific membrane antigen is also an attractive target because of its specificity for prostate tissue, even if PSMA expression in other non-prostatic malignancies or benign conditions may cause incidental false-positive findings [390-394]. A prospective, multi-centre study addressed the use of 68Ga-PSMA PET/CT in patients with newly diagnosed PCa and negative bone scan findings. In 103 eligible patients at increased risk for metastatic LNs prior to surgery, 97 extended pelvic lymph-node dissections (ePLND) were performed, resulting in the identification of 85 LN metastases in 41 patients (42.3%). Positron-emission tomography was positive in 17 patients, resulting in a per-patient-based sensitivity and specificity of 41.5% (95% CI: 26.7–57.8) and 90.9% (95% CI: 79.3–96.6), respectively. A treatment change occurred in 12.6% of patients [395]. Another prospective multi-centre trial investigated the diagnostic accuracy of 18F-DCFPyL ([2-(3-(1-carboxy-5-[(6-18F-fluoropyridine-3-carbonyl)amino]-pentyl)-ureido)-pentanedioic acid] PET/CT for LN staging in 117 patients with primary PCa, prior to

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robot-assisted radical prostatectomy (RARP) with ePLND. 18F-DCFPyL PET/CT showed a high specificity (94.0%; CI: 86.9–97.5%), and a limited sensitivity (41.2%,CI: 19.4–66.5%) for the detection of pelvic LN metastases [396]. This suggests that current PSMA-based PET/CT imaging cannot yet replace diagnostic ePLND. Prostate-specific antigen may be a predictor of a positive PSMA PET/CT. In the primary staging cohort from a meta-analysis [397], however, only 4 studies reported PSMA PET-positivity based on the PSA value, offering no robust estimates of positivity. The tracer uptake is also influenced by the ISUP grade and the PSA level. In a series of 90 patients with primary PCa, tumours with an ISUP grade between 1 and 3 showed significantly lower tracer uptake than tumours with an ISUP grade > 4. Similarly, patients with PSA levels > 10 ng/mL showed significantly higher uptake than those with PSA levels < 10 ng/mL [398]. Comparison between PSMA PET/CT and MRI was recently performed in a systematic review and metaanalysis including 13 studies (n = 1,597) [399]. 68Ga-PSMA was found to have a higher sensitivity and a comparable specificity for staging pre-operative LN metastases in intermediate- and high-risk PCa. The pooled sensitivity and specificity of 68Ga-PSMA PET were 0.65 (95% CI: 0.49–0.79) and 0.94 (95% CI: 0.88–0.97), respectively, while the corresponding values of MRI were 0.41 (95% CI: 0.26–0.57) and 0.92 (95% CI: 0.86–0.95). 68Ga-PSMA PET was potentially a more effective and appropriate imaging modality to predict LN metastasis prior to surgery as indicated by the area under the symmetric receiver-operating characteristic (SROC) curve. Another prospective trial reported superior sensitivity of PSMA PET/CT as compared to MRI for nodal staging of 36 high-risk PCa patients [400]. PSMA PET/CT has a good sensitivity and specificity for LN involvement, possibly impacting clinical decisionmaking. In a recent review and meta-analysis including 37 articles, a subgroup analysis was perfomed in patients undergoing PSMA PET/CT for primary staging. On a per-patient-based analysis, the sensitivity and specificity of 68Ga-PSMA PET were 77% and 97%, respectively, after eLND at the time of RP. On a per-lesionbased analysis, sensitivity and specificity were 75% and 99%, respectively [397]. In summary, PSMA PET/CT is more appropriate in N-staging as compared to MRI, abdominal contrastenhanced CT or choline PET/CT; however, small LN metastases, under the spatial resolution of PET (~5 mm), may still be missed. 5.3.3 M-staging 5.3.3.1 Bone scan 99mTc-Bone scan has been the most widely used method for evaluating bone metastases of PCa. A metaanalysis showed combined sensitivity and specificity of 79% (95% CI: 73–83%) and 82% (95% CI: 78–85%) at patient level and 59% (95% CI: 55–63%) and 75% (95% CI: 71–79%) at lesion level [401]. Bone scan diagnostic yield is significantly influenced by the PSA level, the clinical stage and the tumour ISUP grade and these three factors were the only independent predictors of bone scan positivity in a study of 853 patients [402]. The mean bone scan positivity rate in 23 different series was 2.3% in patients with PSA levels < 10 ng/ mL, 5.3% in patients with PSA levels between 10.1 and 19.9 ng/mL and 16.2% in patients with PSA levels of 20.0–49.9 ng/mL. It was 6.4% in men with organ-confined cancer and 49.5% in men with locally advanced cancers. Detection rates were 5.6% and 29.9% for ISUP grade 2 and > 3, respectively [371]. In two studies, a major Gleason pattern of 4 was found to be a significant predictor of positive bone scan [403, 404]. Bone scanning should be performed in symptomatic patients, independent of PSA level, ISUP grade or clinical stage [371]. 5.3.3.2 Fluoride PET and PET/CT, choline PET/CT and MRI 18F-sodium fluoride (18F-NaF) PET or PET/CT was reported to have similar specificity and superior sensitivity to bone scintigraphy for detecting bone metastases in patients with newly diagnosed high-risk PCa [405, 406]. However, in a prospective study 18F-NaF PET showed no added value over bone scintigraphy in patients with newly diagnosed intermediate- or high-risk PCa and negative bone scintigraphy results [407]. Recently, the interobserver agreement for the detection of bone metastases and the accuracy of 18F-NaF PET/CT in the diagnosis of bone metastases were investigated. Bone metastases were identified in 211 out of 219 patients with an excellent interobserver agreement, demonstrating that 18F-NaF PET/CT is a robust tool for the detection of osteoblastic lesions in patients with PCa [408]. It remains unclear whether choline PET/CT is more sensitive than bone scan but it has higher specificity with fewer indeterminate bone lesions [384, 409, 410]. Diffusion-weighted whole-body and axial MRI are more sensitive than bone scan and targeted conventional radiography in detecting bone metastases in high-risk PCa [411, 412]. Whole-body MRI is also more sensitive and specific than combined bone scan, targeted radiography and abdominopelvic CT [413].

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A meta-analysis found that MRI is more sensitive than choline PET/CT and bone scan for detecting bone metastases on a per-patient basis, although choline PET/CT had the highest specificity [401]. It is of note that choline PET/CT and DW-MRI can also detect visceral and nodal metastases. Bone scan and 18F-NaF PET/CT only assess the presence of bone metastases. 5.3.3.3 Prostate-specific membrane antigen-based PET/CT A systematic review including 12 studies (n = 322) reported high variation in 68Ga-PSMA PET/CT sensitivity for initial staging (range 33–99% median sensitivity on per-lesion analysis 33–92%, and on per-patient analysis 66–91%), with good specificity (per-lesion 82–100%, and per-patient 67–99%), with most studies demonstrating increased detection rates with respect to conventional imaging modalities (bone scan and CT) [414]. Table 5.11 reports the data of the 5 studies including histopathologic correlation. Table 5.11: PSMA PET/CT results in primary staging alone [414] Study Budaus Herlemann Van Leeuwen Maurer Rahbar

Sensitivity (per lesion) 33% 84% 58% 74% 92%

Specificity (per lesion) 100% 82% 100% 99% 92%

PPV (per lesion) 100% 84% 94% 95% 96%

NPV (per lesion) 69% 82% 98% 94% 85%

NPV = negative predictive value; PPV = positive predictive value. One prospective multi-centre study evaluated changes in planned management before and after PSMA PET/CT in 108 intermediate- and high-risk patients referred for primary staging. As compared to conventional staging, additional LNs and bone/visceral metastases were detected in 25% and 6% of patients, respectively [415]; management changes occurred in 21% of patients. A recent retrospective review investigated the risk of metastases identified by 68Ga-PSMA at initial staging in 1,253 patients (high-risk disease in 49.7%) [416]. Metastatic disease was identified by PSMA PET/CT in 12.1% of men, including 8.2% with a PSA level of < 10 ng/mL and 43% with a PSA level of > 20 ng/mL. Lymph node metastases were suspected in 107 men, with 47.7% outside the boundaries of an ePLND. Bone metastases were identified in 4.7%. In men with intermediate-risk PCa metastases were identified in 5.2%, compared to 19.9% with high-risk disease. In the PSMA PET/CT prospective multi-centre study in patients with high-risk PCa before curativeintent surgery or RT (proPSMA), 302 patients were randomly assigned to conventional imaging with CT and bone scintigraphy or 68Ga-PSMA-11 PET/CT. The primary outcome focused on the accuracy of first-line imaging for the identification of pelvic LN or distant metastases, using a predefined reference standard consisting of histopathology, imaging, and biochemistry at 6-month follow-up. Accuracy of 68Ga-PSMA PET/CT was 27% (95% CI: 23–31) higher than that of CT and bone scintigraphy (92% [88–95] vs. 65% [60–69]; p < 0.0001). Conventional imaging had a lower sensitivity (38% [24–52] vs. 85% [74–96]) and specificity (91% [85–97] vs. 98% [95–100]) than PSMA PET/CT. Furthermore, 68Ga-PSMA PET/CT scan prompted management change more frequently as compared to conventional imaging (41 [28%] men [21–36] vs. 23 [15%] men [10–22], p = 0.08), with less equivocal findings (7% [4–13] vs. 23% [17–31]) and lower radiation exposure (8.4 mSv vs. 19.2 mSv; p < 0.001) [417]. 5.3.4 Summary of evidence and practical considerations on initial N/M staging The field of non-invasive N- and M-staging of PCa patients is evolving very rapidly. Evidence shows that choline PET/CT, PSMA PET/CT and MRI provide a more sensitive detection of LN- and bone metastases than the classical work-up with bone scan and abdominopelvic CT. In view of the evidence offered by the randomised, multi-centre proPSMA trial [417], replacing bone scan and abdominopelvic CT by more sensitive imaging modalities may be a consideration in patients with high-risk PCa undergoing initial staging. However, in absence of prospective studies demonstrating survival benefit, caution must be used when taking therapeutic decisions [418]. The prognosis and ideal management of patients diagnosed as metastatic by these more sensitive tests is unknown. In particular, it is unclear whether patients with metastases detectable only with PET/CT or MRI should be managed using systemic therapies, or whether they should be subjected to aggressive local and metastases-directed therapies [419]. Results from RCTs evaluating the management and outcome of patients with (and without) metastases detected by choline PET/CT, PSMA PET/CT and MRI are awaited before a decision can be made to treat patients based on the results of these tests [420].

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5.3.5

Summary of evidence and guidelines for staging of prostate cancer

Summary of evidence LE PSMA PET/CT is more accurate for staging than CT and bone scan but to date no outcome data exist 1b to inform subsequent management.

Any risk group staging Use pre-biopsy MRI for local staging information. Low-risk localised disease Do not use additional imaging for staging purposes. Intermediate-risk disease In ISUP grade > 3, include at least cross-sectional abdominopelvic imaging and a bonescan for metastatic screening. High-risk localised disease/locally advanced disease Perform metastatic screening including at least cross-sectional abdominopelvic imaging and a bone-scan.

5.4

Strength rating Weak Strong Weak

Strong

Estimating life expectancy and health status

5.4.1 Introduction Evaluation of life expectancy and health status is important in clinical decision-making for screening, diagnosis, and treatment of PCa. Prostate cancer is common in older men (median age 68) and diagnoses in men > 65 will result in a 70% increase in annual diagnosis by 2030 in Europe and the USA [421, 422]. Active treatment mostly benefits patients with intermediate- or high-risk PCa and longest expected survival. In localised disease, over 10 years life expectancy is considered mandatory for any benefit from local treatment and an improvement in CSS may take longer to become apparent. Older age and worse baseline health status have been associated with a smaller benefit in PCa-specific mortality (PCSM) and life expectancy of surgery vs. active surveillance (AS) [423]. Although in a RCT the benefit of surgery with respect to death from PCa was largest in men < 65 years of age (RR: 0.45), RP was associated with a reduced risk of metastases and use of androgen deprivation therapy (ADT) among older men (RR: 0.68 and 0.60, respectively) [424]. External beam radiotherapy shows similar cancer control regardless of age, assuming a dose of > 72 Gy when using intensity-modulated or image-guided RT [425]. Older men have a higher incidence of PCa and may be under-treated despite the high overall mortality rates [426, 427]. Of all PCa-related deaths 71% occur in men aged > 75 years [428], probably due to the higher incidence of advanced disease and death from PCa despite higher death rates from competing causes [429-431]. In the USA, only 41% of patients aged > 75 years with intermediate- and high-risk disease received curative treatment compared to 88% aged 65–74 [432]. 5.4.2 Life expectancy Life expectancy tables for European men are available online: https://ec.europa.eu/eurostat/web/productsdatasets/-/tps00205. Survival may be variable and therefore estimates of survival must be individualised. Gait speed is a good single predictive method of life expectancy (from a standing start, at usual pace, generally over 6 meters). For men at age 75, 10-year survival ranged from 19% < 0.4 m/s to 87%, for > 1.4 m/s [433].

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Figure 5.2: Predicted Median Life Expectancy by Age and Gait Speed for males* [433]

*Figure reproduced with permission of the publisher, from Studenski S, et al. JAMA 2011 305(1)50. 5.4.3 Health status screening Heterogeneity increases with advancing age, so it is important to use measures other than just age or performance status (PS) when considering treatment options. The International SIOG PCa Working Group recommends that treatment for adults over 70 years of age should be based on a systematic evaluation of health status using the G8 (Geriatric 8) screening tool (see Table 5.12) [134]. This tool helps to discriminate between those who are fit and those with frailty, a syndrome of reduced ability to respond to stressors. Patients with frailty have a higher risk of mortality and negative side effects of cancer treatment [434]. Healthy patients with a G8 score > 14 or vulnerable patients with reversible impairment after resolution of their geriatric problems should receive the same treatment as younger patients. Frail patients with irreversible impairment should receive adapted treatment. Patients who are too ill should receive only palliative treatment (see Figure 5.3) [134]. Patients with a G8 score < 14 should undergo a comprehensive geriatric assessment (CGA) as this score is associated with 3-year mortality. A CGA is a multi-domain assessment that includes co-morbidity, nutritional status, cognitive and physical function, and social supports to determine if impairments are reversible [435]. A systematic review of the effect of geriatric evaluation for older cancer patients showed improved treatment tolerance and completion [436]. The Clinical Frailty Scale (CFS) is another screening tool for frailty (see Table 5.4.2) [437]. Although not frequently used in the cancer setting, it is considered to be a common language for expressing degree of frailty. The scale runs from 1 to 9, with higher scores indicating increasing frailty. Patients with a higher CFS score have a higher 30-day mortality after surgery and are less likely to be discharged home [438]. It is important to use a validated tool to identify frailty, such as the G8 or CFS, as clinical judgement has been shown to be poorly predictive of frailty in older patients with cancer [439]. 5.4.3.1 Co-morbidity Co-morbidity is a major predictor of non-cancer-specific death in localised PCa treated with RP and is more important than age [440, 441]. Ten years after not receiving active treatment for PCa, most men with a high co-morbidity score had died from competing causes, irrespective of age or tumour aggressiveness [440]. Measures for co-morbidity include: Cumulative Illness Score Rating-Geriatrics (CISR-G) [442, 443] (Table 5.13) and Charlson Co-morbidity Index (CCI) [444]. 5.4.3.2 Nutritional status Malnutrition can be estimated from body weight during the previous 3 months (good nutritional status < 5% weight loss; risk of malnutrition: 5–10% weight loss; severe malnutrition: > 10% weight loss) [445].

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5.4.3.3 Cognitive function Cognitive impairment can be screened for using the mini-COG (https://mini-cog.com/) which consists of three-word recall and a clock-drawing test and can be completed within 5 minutes. A score of < 3/5 indicates the need to refer the patient for full cognitive assessment. Patients with any form of cognitive impairment (e.g., Alzheimer’s or vascular dementia) may need a capacity assessment of their ability to make an informed decision, which is an increasingly important factor in health status assessment [446-448]. Cognitive impairment also predicts risk of delirium, which is important for patients undergoing surgery [449]. 5.4.3.4 Physical function Measures for overall physical functioning include: Karnofsky score and ECOG scores [450]. Measures for dependence in daily activities include: Activities of Daily Living (ADL; basic activities) and Instrumental Activities of Daily Living (IADL; activities requiring higher cognition and judgement) [451-453]. 5.4.3.5 Shared decision-making The patient’s own values and preferences should be taken into account as well as the above factors. A shared decision-making process also involves anticipated changes to quality of life (QoL) functional ability, and a patient’s hopes, worries and expectations about the future [454]. Particularly in older and frail patients, these aspects should be given equal importance to disease characteristics during the decision-making process [455]. Older patients may also wish to involve family members, and this is particularly important where cognitive impairment exists. 5.4.4 Conclusion Individual life expectancy, health status, frailty, and co-morbidity, not only age, should be central in clinical decisions on screening, diagnostics, and treatment for PCa. A life expectancy of 10 years is most commonly used as a threshold for benefit of local treatment. Older men may be undertreated. Patients aged 70 years of age or older who have frailty should receive a comprehensive geriatric assessment. Resolution of impairments in vulnerable men allows a similar urological approach as in fit patients. Table 5.12: G8 screening tool (adapted from [456])

A

B

C

D

E

F G

H

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Items Has food intake declined over the past 3 months due to loss of appetite, digestive problems, chewing, or swallowing difficulties?

Possible responses (score) 0 = severe decrease in food intake 1 = moderate decrease in food intake 2 = no decrease in food intake Weight loss during the last 3 months? 0 = weight loss > 3 kg 1 = does not know 2 = weight loss between 1 and 3 kg 3 = no weight loss Mobility? 0 = bed or chair bound 1 = able to get out of bed/chair but does not go out 2 = goes out Neuropsychological problems? 0 = severe dementia or depression 1 = mild dementia 2 = no psychological problems 0 = BMI < 19 BMI? (weight in kg)/(height in m2) 1 = BMI 19 to < 21 2 = BMI 21 to < 23 3 = BMI > 23 Takes more than three prescription drugs per 0 = yes day? 1 = no 0.0 = not as good In comparison with other people of the same age, how does the patient consider his/her health 0.5 = does not know status? 1.0 = as good 2.0 = better Age 0 = > 85 1 = 80-85 2 = < 80 Total score 0-17

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Figure 5.3: Decision tree for health status screening (men > 70 years)** [134] Screening by G8 and mini-COG

G8 score > 14/17 no geriatric evaluation is needed

TM*

G8 score ≤ 14/17 a full geriatric evaluation is mandatory

- Abnormal ADL: 1 or 2 - Weight loss 5-10% - Comorbidities CISR-G grades 1-2

- Abnormal ADL: > 2 - Weight loss > 10% - Comorbidities CISR-G grades 3-4

Geriatric assessment then geriatric intervention

Group 1 Fit

Group 2 Vulnerable

Group 3 Frail

Mini-COGTM = Mini-COGTM cognitive test; ADLs = activities of daily living; CIRS-G = Cumulative Illness Rating Score - Geriatrics; CGA = comprehensive geriatric assessment. *F  or Mini-COGTM, a cut-off point of 65 years who were not given curative treatment, most men with a CCI score > 2 had died from competing causes at 10 years follow-up regardless of their age at time of diagnosis. Tumour aggressiveness had little impact on OS suggesting that patients could have been spared biopsy and diagnosis of cancer. Men with a CCI score < 1 had a low risk of death at 10 years, especially for wellor moderately-differentiated lesions [440]. This highlights the importance of assessing co-morbidity before considering a biopsy. In screening-detected localised PCa the lead-time bias is likely to be greater. Mortality from untreated screen-detected PCa in patients with ISUP grade 1–2 might be as low as 7% at 15 years followup [465]. Consequently, approximately 45% of men with PSA-detected PCa are suitable for close follow-up through a robust surveillance programme. There are two distinct strategies for conservative management that aim to reduce over-treatment: AS and Watchful waiting (WW) (Table 6.1.1). 6.1.1.1 Definitions Active surveillance aims to avoid unnecessary treatment in men with clinically localised PCa who do not require immediate treatment, but at the same time achieve the correct timing for curative treatment in those who eventually do [466]. Patients remain under close surveillance through structured surveillance programmes with regular follow-up consisting of PSA testing, clinical examination, mpMRI imaging and repeat prostate biopsies, with curative treatment being prompted by pre-defined thresholds indicative of potentially life-threatening disease which is still potentially curable, while considering individual life expectancy. Watchful waiting refers to conservative management for patients deemed unsuitable for curative treatment from the outset, and patients are clinically ‘watched’ for the development of local or systemic progression with (imminent) disease-related complaints, at which stage they are then treated palliatively according to their symptoms in order to maintain QoL. Table 6.1.1: Definitions of active surveillance and watchful waiting [465]

Treatment intent Follow-up Assessment/markers used

Life expectancy Aim Comments

Active surveillance Curative Pre-defined schedule DRE, PSA, mpMRI, re-biopsy

> 10 years Minimise treatment-related toxicity without compromising survival Low-risk patients

Watchful waiting Palliative Patient-specific Not pre-defined, but dependent on development of symptoms of progression < 10 years Minimise treatment-related toxicity Can apply to patients with all stages

DRE = digital rectal examination; PSA = prostate-specific antigen; mpMRI = multiparametric magnetic resonance imaging. 6.1.1.2 Active surveillance No formal RCT is available comparing this modality to standard treatment. The Prostate Testing for Cancer and Treatment (ProtecT) trial is discussed later as it is not a formal AS strategy but rather active monitoring (AM), which is a significantly less stringent surveillance strategy in terms of clinical follow-up, imaging and repeat biopsies [467]. Several cohorts have investigated AS in organ-confined disease, the findings of which were summarised in a systematic review [468]. More recently, the largest prospective series of men with low-risk PCa managed by AS was published [469]. Table 6.1.2 summarises the results of selective AS cohorts. It is clear that the long-term OS and CSS of patients on AS are extremely good. However, more than one-third of patients are ‘reclassified’ during follow-up, most of whom undergo curative treatment due to disease upgrading, increase in disease extent, disease stage, progression or patient preference. There is considerable variation and heterogeneity between studies regarding patient selection and eligibility, follow-up policies (including frequency and type of imaging such as mpMRI imaging, type and frequency of repeat prostate biopsies, such as MRI-targeted biopsies or transperineal template biopsies, use of PSA kinetics and density, and frequency of clinical followup), when active treatment should be instigated (i.e. reclassification criteria) and which outcome measures should be prioritised [466]. These will be discussed further in section 6.2.1.

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Table 6.1.2: Active surveillance in screening-detected prostate cancer Studies

N

Median FU (mo)

Van As, et al. 2008 [470] Carter, et al. 2007 [471] Adamy, et al. 2011 [472] Soloway, et al. 2010 [473] Roemeling, et al. 2007 [474] Khatami, et al. 2007 [475] Klotz, et al. 2015 [476] Tosoian, et al. 2015 [469] Total

326 407 533-1,000 99 278 270 993 1,818 4,724-5,191

22 41 48 45 41 63 77 60 46.5

pT3 in RP patients* 10-year OS (%) 8/18 (44%) 98 10/49 (20%) 98 4/24 (17%) 90 0/2 100 89 n.r. 85 93 93

10-year CSS (%) 100 100 99 100 100 100 98.1 99.9 99

* Patients receiving active therapy following initial active surveillance. CSS = cancer-specific survival; FU = follow-up; mo = months; n = number of patients; n.r. = not reported; OS = overall survival; RP = radical prostatectomy. 6.1.1.3 Watchful Waiting 6.1.1.3.1 Outcome of watchful waiting compared with active treatment The SPCG-4 study was a RCT from the pre-PSA era, randomising patients to either WW or RP (Table 6.1.3) [477]. The study found RP to provide superior CSS, OS and progression-free survival (PFS) compared to WW at a median follow-up of 23.6 years (range 3 weeks–28 years). The PIVOT trial was a RCT conducted in the early PSA era and made a similar comparison between RP vs. observation in 731 men (50% with nonpalpable disease) [478] but in contrast to the SPCG-4, it found little to no benefit of RP (cumulative incidence of all-cause death, RP vs. observation: 68% vs. 73%; RR: 0.92, 95% CI: 0.84–1.01) within a median followup period of 18.6 years (interquartile range, 16.6 to 20 years). Exploratory subgroup analysis showed that the borderline benefit from RP was most marked for intermediate-risk disease (RR: 0.84, 95% CI: 0.73–0.98) but there was no benefit in patients with low- or high-risk disease. Overall, no adverse effects on HRQoL and psychological well-being was apparent in the first years [479]. However, one of the criticisms of the PIVOT trial is the relatively high overall mortality rate in the WW group (73% at a median follow-up period of 18.6 years (interquartile range, 16.6 to 20.0 years) compared with more contemporary series. Table 6.1.3: Outcome of SPCG-4 at a median follow-up of 23.6 years [477] RP (n = 348) (%) Disease-specific mortality Overall mortality Metastatic progression

19.6 71.9 26.6

Watchful waiting (n = 348) (%) 31.3 83.8 43.3

Relative risk (95% CI) 0.55 (0.41–0.74) 0.74 (0.62–0.87) 0.54 (0.42–0.70)

p-value < 0.001 < 0.001 < 0.001

CI = confidence interval; RP = radical prostatectomy. 6.1.1.4 The ProtecT study The ProtecT trial randomised 1,643 patients into three arms: active treatment with either RP or EBRT, and AM [467]. In this AM schedule patients with a PSA rise of more than 50% in 12 months underwent a repeat biopsy, but none had systematic repeat biopsies. Fifty-six percent of patients had low-risk disease, with 90% having a PSA < 10 ng/mL, 77% ISUP grade 1 (20% ISUP grade 2–3), and 76% T1c, while the other patients had mainly intermediate-risk disease. After 10 years of follow-up, CSS was the same between those actively treated and those on AM (99% and 98.8%, respectively), as was the OS. Only metastatic progression differed (6% in the AM group as compared to 2.6% in the treated group). The key finding was that AM was as effective as active treatment at 10 years, at a cost of increased progression and double the metastatic risk. Metastases remained rare (6%), but more frequent than seen with AS protocols; probably driven by differences in intensity of monitoring and patient selection. It is important to note that the AM arm in ProtecT represented an intermediate approach between contemporary AS protocols and WW in terms of a monitoring strategy based almost entirely on PSA measurements alone; there was no use of mpMRI scan, either at recruitment or during the monitoring period, nor was there any protocol-mandated repeat prostate biopsies at regular intervals. In addition, approximately 40% of randomised patients had intermediate-risk disease. Nevertheless, the ProtecT study has reinforced the role of deferred active treatment (i.e. either AS or some form of initial AM) as a feasible alternative to active curative interventions in patients with low-grade and

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low-stage disease. Beyond 10 years, no data is available, as yet, although AS is likely to give more reassurance especially in younger men, based on more accurate risk stratification at recruitment and more stringent criteria regarding follow-up, imaging, repeat biopsy and reclassification. Individual life expectancy must be evaluated before considering any active treatment in low-risk patients and in those with up to 10 years’ individual life expectancy. 6.1.2 Radical prostatectomy 6.1.2.1 Introduction The goal of RP by any approach is the eradication of cancer while, whenever possible, preserving pelvic organ function [480]. The procedure involves removing the entire prostate with its capsule intact and SVs, followed by vesico-urethral anastomosis. Surgical approaches have expanded from perineal and retropubic open approaches to laparoscopic and robotic-assisted techniques; anastomoses have evolved from Vest approximation sutures to continuous suture watertight anastomoses under direct vision and mapping of the anatomy of the dorsal venous complex (DVC) and cavernous nerves has led to excellent visualisation and potential for preservation of erectile function [481]. The main results from multi-centre RCTs involving RP are summarised in Table 6.1.4. Table 6.1.4: Oncological results of radical prostatectomy in organ-confined disease in RCTs Study

Acronym

Population

Bill-Axelson, et al. 2018 [477] Wilt, et al. 2017 [482]

SPCG-4

Pre-PSA era

PIVOT

ProtecT

Hamdy, et al. 2016 [467]

Treatment period 1989-1999

Median FU (mo) 283

Early years of PSA testing

1994-2002

152

Screened population

1999-2009

120

Risk category

CSS (%)

Low risk and Intermediate risk Low risk Intermediate risk

80.4 (at 23 yr.) 95.9 91.5 (at 19.5 yr.) 99 (at 10 yr.)

Mainly low- and intermediate risk

CSS = cancer-specific survival; FU = follow-up; mo = months; PSA = prostate-specific antigen; yr. = year. 6.1.2.2 Pre-operative preparation 6.1.2.2.1 Pre-operative patient education As before any surgery appropriate education and patient consent is mandatory prior to RP. Peri-operative education has been shown to improve long-term patient satisfaction following RP [483]. Augmentation of standard verbal and written educational materials such as use of interactive multimedia tools [484, 485] and pre-operative patient-specific 3D printed prostate models has been shown to improve patient understanding and satisfaction and should be considered to optimise patient-centred care [486]. Pre-operative pelvic floor exercises Although many patients who have undergone RP will experience a return to urinary continence [487], temporary urinary incontinence is common early after surgery, reducing QoL. Pre-operative pelvic floor exercises (PFE) with, or without, biofeedback have been used with the aim of reducing this early post-operative incontinence. A systematic review and meta-analysis of the effect of pre-RP PFE on post-operative urinary incontinence showed a significant improvement in incontinence rates at 3 months post-operatively with an OR of 0.64 (p = 0.005), but not at 1 month or 6 months [488]. Pre-operative PFE may therefore provide some benefit, however the analysis was hampered by the variety of PFE regimens and a lack of consensus on the definition of incontinence. Prophylactic antibiotics Prophylactic antibiotics should be used; however no high-level evidence is available to recommend specific prophylactic antibiotics prior to RP (See EAU Urological Infections Guidelines). In addition, as the susceptibility of bacterial pathogens and antibiotic availability varies worldwide, any use of prophylactic antibiotics should adhere to local guidelines. Neoadjuvant androgen deprivation therapy Several RCTs have analysed the impact of neoadjuvant ADT before RP, most of these using a 3-month period. The main findings were summarised in a Cochrane review [489]. Neoadjuvant ADT is associated with a decreased rate of pT3 (downstaging), decreased positive margins, and a lower incidence of positive LNs. These benefits are greater with increased treatment duration (up to 8 months). However, since neither the PSA

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relapse-free survival nor CSS were shown to improve, neoadjuvant ADT should not be considered as standard clinical practice. One recent RCT compared neoadjuvant luteinising hormone-releasing hormone (LHRH) alone vs. LHRH plus abiraterone plus prednisone prior to RP in 65 localised high-risk PCa patients [490]. Patients in the combination arm were found to have both significantly lower tumour volume and significantly lower BCR at > 4 years follow-up (p = 0.0014). Further supportive evidence is required before recommending combination neoadjuvant therapy including abiraterone prior to RP. 6.1.2.3 Surgical techniques Prostatectomy can be performed by open-, laparoscopic- or robot-assisted (RARP) approaches. The initial open technique of RP described by Young in 1904 was via the perineum [481] but suffered from a lack of access to pelvic LNs. If lymphadenectomy is required during perineal RP it must be done via a separate open retropubic (RRP) or laparoscopic approach. The open retropubic approach was popularised by Walsh in 1982 following his anatomical description of the DVC, enabling its early control and of the cavernous nerves, permitting a bilateral nerve-sparing procedure [491]. This led to the demise in popularity of perineal RP and eventually to the first laparoscopic RP reported in 1997 using retropubic principles, but performed transperitoneally [492]. The initial 9 cases averaged 9.4 hours, an indication of the significant technical and ergonomic difficulties of the technique. Most recently, RARP was introduced using the da Vinci Surgical System® by Binder in 2002 [493]. This technology combined the minimally-invasive advantages of laparoscopic RP with improved surgeon ergonomics and greater technical ease of suture reconstruction of the vesico-urethral anastomosis and has now become the preferred minimally-invasive approach, when available. In a randomised phase III trial, RARP was shown to have reduced admission times and blood loss, but not earlier (12 weeks) functional or oncological outcomes compared to open RP [494]. An updated analysis with follow-up at 24 months did not reveal any significant differences in functional outcomes between the approaches [495]. Increased surgical experience has lowered the complication rates of RP and improved cancer cure [461-464]. Lower rates of positive surgical margins for high-volume surgeons suggest that experience and careful attention to surgical details, can improve cancer control with RP [496-498]. There is a lack of studies comparing the different surgical modalities for these longer-term outcomes [460, 479, 482, 499]. A systematic review and meta-analysis of non-RCTs demonstrated that RARP had lower peri-operative morbidity and a reduced risk of positive surgical margins compared with laparoscopic prostatectomy (LRP), although there was considerable methodological uncertainty [500]. There was no evidence of differences in urinary incontinence at 12 months and there was insufficient evidence to draw conclusions based on differences in cancer-related, patient-driven or erectile dysfunction (ED) outcomes. Another systematic review and meta-analysis included two small RCTs comparing RARP vs. LRP [501]. The results suggested higher rates of return of erectile function (RR: 1.51, 95% CI: 1.19–1.92) and return to continence function (RR: 1.14, 95% CI: 1.04–1.24) in the RARP group. However, a recent Cochrane review comparing either RARP or LRP vs. open RP included two RCTs and found no significant differences between the comparisons for oncological-, urinary- and sexual function outcomes, although RARP and LRP both resulted in statistically significant improvements in duration of hospital stay and blood transfusion rates over open RP [502]. Therefore, no surgical approach can be recommended over another. Outcome after prostatectomy has been shown to be dependent on both surgeon [503] as well as hospital volume [504]. Although various volume criteria have been set worldwide, the level of evidence is insufficient to pinpoint a specific lower volume limit. 6.1.2.3.1 Robotic anterior versus Retzius-sparing dissection Robot-assisted RP has typically been performed via the anterior approach, first dropping the bladder to expose the space of Retzius. However, the posterior approach (Retzius-sparing [RS-RARP]) has been used to minimise injury to support structures surrounding the prostate. Galfano et al., first described RS-RARP in 2010 [505]. This approach commences dissection posteriorly at the pouch of Douglas, first dissecting the SVs and progressing caudally behind the prostate. All of the anterior support structures are avoided, giving rise to the hypothetical mechanism for improved early post-operative continence. Retzius-sparing-RARP thus offers the same potential advantage as the open perineal approach, but without disturbance of the perineal musculature. Retzius-sparing-RARP has been recently investigated in RCTs leading to four systematic reviews and meta-analyses [506-508] including a 2020 Cochrane systematic review [509] and a large propensity score matched analysis [510]. The Cochrane review used the most rigorous methodology and analysed 5 RCTs with 502 patients. It found with moderate certainty that RS-RARP improved continence at 1 week post catheter removal compared to standard RARP (RR: 1.74). Continence may also be improved at 3 months

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post-operatively (RR: 1.33), but this was based on low-certainty data. Continence outcomes appeared to equalise by 12 months (RR: 1.01). These findings matched those of the other systematic reviews. However, a significant concern was that RS-RARP appears to increase the risk of positive margins (RR: 1.95) but this was also low-certainty evidence. A single-surgeon propensity score matched analysis of 1,863 patients reached the same conclusion as the systematic reviews regarding earlier return to continence but did not show data on margin status [510]. Based on these data, recommendations cannot be made for one technique over another. However, the trade-offs between the risks of a positive margin vs. earlier continence recovery should be discussed with prospective patients. Furthermore, no high level evidence is available on high-risk disease with some concerns that RS-RARP may confer an increased positive margin rate based on pT3 results. In addition, RS-RARP may be more technically challenging in various scenarios such as anterior tumours, post-TURP, a grossly enlarged gland, or a bulky median lobe [511]. 6.1.2.3.2 Pelvic lymph node dissection A recent systematic review demonstrated that performing PLND during RP failed to improve oncological outcomes, including survival [512]. Moreover, a RCT failed to show a benefit of an extended approach vs. a limited PLND on early oncologic outcomes [513]. However, it is generally accepted that eLND provides important information for staging and prognosis which cannot be matched by any other currently available procedure [512]. Extended LND includes removal of the nodes overlying the external iliac artery and vein, the nodes within the obturator fossa located cranially and caudally to the obturator nerve, and the nodes medial and lateral to the internal iliac artery. With this template, 94% of patients are correctly staged [514]. The individual risk of patients harbouring positive LNs can be estimated based on validated nomograms. The Briganti nomogram [381, 382], the Roach formula [515] or the Partin and MSKCC nomograms [516] have shown similar diagnostic accuracy in predicting LN invasion. These nomograms have all been developed in the preMRI setting based on systematic random biopsy. A risk of nodal metastases over 5% can be used to identify candidates for nodal sampling by eLND during RP [517-519]. An updated nomogram has been externally validated in men diagnosed based on mpMRI followed by MRItargeted biopsy [382]. Based on this nomogram patients can be spared an ePLND if their risk of nodal involvement is less than 7%; which would result in missing only 1.5% of patients with nodal invasion [382, 520]. This 7% cutoff is comparable to the 5% cutoff of the Briganti nomogram in patients diagnosed by systematic random biopsy alone. Therefore, this novel nomogram and a 7% threshold should be used after MRI-targeted biopsy to identify candidates for eLND [521]. 6.1.2.3.3 Sentinel node biopsy analysis The rationale for a sentinel node biopsy (SNB) is based on the concept that a sentinel node is the first to be involved by migrating tumour cells. Therefore, when this node is negative it is possible to avoid an ePLND. There is heterogeneity and variation in techniques in relation to SNB (e.g. the optimal tracer) but a multidisciplinary collaborative endeavour attempted to standardise definitions, thresholds and strategies in relation to techniques of SNB using consensus methods [522]. Intraprostatic injections of indocyanine green (ICG) have been used to visualise prostate-related LNs during lymphadenectomy. In a randomised comparison, Harke et al., found more cancer containing LNs in men that underwent a LN dissection guided by ICG but no difference in BCR at 22.9 month follow-up [523]. A systematic review showed a sensitivity of 95.2% and NPV of 98.0% for SNB in detecting men with metastases at eLND [524]. However, there is still insufficient high-quality evidence supporting oncological effectiveness of SNB for nodal staging. Sentinel node biopsy is therefore still considered as an experimental nodal staging procedure. 6.1.2.3.4 Prostatic anterior fat pad dissection and histologic analysis Several multi-centre and large single-centre series have shown the presence of lymphoid tissue within the fat pad anterior to the endopelvic fascia; the prostatic anterior fat pad (PAFP) [525-531]. This lymphoid tissue is present in 5.5–10.6% of cases and contains metastatic PCa in up to 1.3% of intermediate- and high-risk patients. When positive, the PAFP is often the only site of LN metastasis. The PAFP is therefore a rare but recognised route of spread of disease. Unlike PLND, there is no morbidity associated with removal of the PAFP. The PAFP is always removed at RP for exposure of the endopelvic fascia and should be sent for histologic analysis as per all removed tissue.

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6.1.2.3.5 Management of the dorsal venous complex Since the description of the anatomical open RP by Walsh and Donker in the 1980s, various methods of controlling bleeding from the DVC have been proposed to optimise visualisation [491]. In the open setting, blood loss and transfusion rates have been found to be significantly reduced when ligating the DVC prior to transection [532]. However, concerns have been raised regarding the effect of prior DVC ligation on apical margin positivity and continence recovery due to the proximity of the DVC to both the prostatic apex and the urethral sphincter muscle fibres. In the robotic-assisted laparoscopic technique, due to the increased pressure of pneumoperitoneum, whether prior DVC ligation was used or not, blood loss was not found to be significantly different in one study [533]. In another study, mean blood loss was significantly less with prior DVC ligation (184 vs. 176 mL, p = 0.033), however it is debatable whether this was clinically significant [534]. The positive apical margin rate was not different, however, the latter study showed earlier return to full continence at 5 months post-operatively in the no prior DVC ligation group (61% vs. 40%, p < 0.01). Ligation of the DVC can be performed with standard suture or using a vascular stapler. One study found significantly reduced blood loss (494 mL vs. 288 mL) and improved apical margin status (13% vs. 2%) when using the stapler [535]. Given the relatively small differences in outcomes, the surgeon’s choice to ligate prior to transection or not, or whether to use sutures or a stapler, will depend on their familiarity with the technique and the equipment available. 6.1.2.3.6 Nerve-sparing surgery During prostatectomy, preservation of the neurovascular bundles with parasympathetic nerve branches of the pelvic plexus may spare erectile function [536, 537]. Although age and pre-operative function may remain the most important predictors for postoperative erectile function, nerve-sparing has also been associated with improved continence outcomes and may therefore still be relevant for men with poor erectile function [538, 539]. The association with continence may be mainly due to the dissection technique used during nerve-sparing surgery, and not due to the preservation of the nerve bundles themselves [538]. Extra-, inter-, and intra-fascial dissection planes can be planned, with those closer to the prostate and performed bilaterally associated with superior (early) functional outcomes [540-543]. Furthermore, many different techniques are propagated such as retrograde approach after anterior release (vs. antegrade), and athermal and traction-free handling of bundles [544-546]. Nerve-sparing does not compromise cancer control if patients are carefully selected depending on tumour location, size and grade [547-549]. 6.1.2.3.7 Lymph-node-positive patients during radical prostatectomy Although no RCTs are available, data from prospective cohort studies comparing survival of pN+ patients (as defined following pathological examination after RP) support that RP may have a survival benefit over abandonment of RP in node-positive cases [550]. As a consequence there is no role for performing frozen section of suspicious LNs. 6.1.2.3.8 Removal of seminal vesicles The more aggressive forms of PCa may spread directly into the SVs. For oncological clearance, the SVs have traditionally been removed intact with the prostate specimen [551]. However, in some patients the tips of the SVs can be challenging to dissect free. Furthermore, the cavernous nerves run past the SV tips such that indiscriminate dissection of the SV tips could potentially lead to ED [552]. However, a RCT comparing nervesparing RP with and without a SV-sparing approach found no difference in margin status, PSA recurrence, continence or erectile function outcomes. Another study of 71 consecutive RPs showed no cancer in any of the distal 1 cm of SVs, even in 12 patients with SV invasion [553]. Whilst complete SV removal should be the default, preservation of the SV tips may be considered in cases of low risk of involvement. 6.1.2.3.9 Techniques of vesico-urethral anastomosis Following prostate removal, the bladder neck is anastomosed to the membranous urethra. The objective is to create a precisely aligned, watertight, tension-free, and stricture-free anastomosis that preserves the integrity of the intrinsic sphincter mechanism. Several methods have been described, based on the direct or indirect approach, the type of suture (i.e. barbed vs. non-barbed/monofilament), and variation in suturing technique (e.g., continuous vs. interrupted, or single-needle vs. double-needle running suture). The direct vesico-urethral anastomosis, which involves the construction of a primary end-to-end inter-mucosal anastomosis of the bladder neck to the membranous urethra by using 6 interrupted sutures placed circumferentially, has become the standard method of reconstruction for open RP [554].

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The development of laparoscopic- and robotic-assisted techniques to perform RP have facilitated the introduction of new suturing techniques for the anastomosis. A systematic review and meta-analysis [555] compared unidirectional barbed suture vs. conventional non-barbed suture for vesico-urethral anastomosis during robotic-assisted laparoscopic prostatectomy (RALP). The review included 3 RCTs and found significantly reduced anastomosis time, operative time and posterior reconstruction time in favour of the unidirectional barbed suture technique, but there were no differences in post-operative leak rate, length of catheterisation and continence rate. However, no definitive conclusions could be drawn due to the relatively low quality of the data. In regard to suturing technique, a systematic review and meta-analysis compared continuous vs. interrupted suturing for vesico-urethral anastomosis during RP [556]. The study included only one RCT with 60 patients [557]. Although the review found slight advantages for continuous suturing over interrupted suturing in terms of catheterisation time, anastomosis time and rate of extravasation, the overall quality of evidence was low and no clear recommendations were possible. A recent RCT [558] compared the technique of suturing using a single absorbable running suture vs. a double-needle single-knot running suture (i.e. Van Velthoven technique) in laparoscopic RP [559]. The study found slightly reduced anastomosis time with the single running suture technique, but anastomotic leak, stricture, and continence rates were similar. Overall, although there are a variety of approaches, methods and techniques for performing the vesico-urethral anastomosis, no clear recommendations are possible due to the lack of high-certainty evidence. In practice, the chosen method should be based on surgeon experience and individual preference [554-565]. 6.1.2.3.10 Bladder neck management Bladder neck mucosal eversion Some surgeons perform mucosal eversion of the bladder neck as its own step in open RP with the aim of securing a mucosa-to-mucosa vesico-urethral anastomosis and avoiding anastomotic stricture. Whilst bringing bladder and urethral mucosa together by the everted bladder mucosa covering the bladder muscle layer, this step may actually delay healing of the muscle layers. An alternative is to simply ensure bladder mucosa is included in the full thickness anastomotic sutures. A non-randomised study of 211 patients with and without bladder neck mucosal eversion showed no significant difference in anastomotic stricture rate [566]. The strongest predictor of anastomotic stricture in RP is current cigarette smoking [567]. Bladder neck preservation Whilst the majority of urinary continence is maintained by the external urethral sphincter at the membranous urethra (see below), a minor component is contributed by the internal lissosphincter at the bladder neck [568]. Preservation of the bladder neck has therefore been proposed to improve continence recovery post-RP. A RCT assessing continence recovery at 12 months and 4 years showed improved objective and subjective urinary continence in both the short- and long term without any adverse effect on oncological outcome [569]. These findings were confirmed by a systematic review [570]. However, concern remains regarding margin status for cancers located at the prostate base. A systematic review addressing site-specific margin status found a mean base-specific positive margin rate of 4.9% with bladder neck preservation vs. only 1.9% without [568]. This study was inconclusive, but it would be sensible to exercise caution when considering bladder neck preservation if significant cancer is known to be at the prostate base. Bladder neck preservation should be performed routinely when the cancer is distant from the base. However, bladder neck preservation cannot be performed in the presence of a large median lobe or a previous TURP. 6.1.2.3.11 Urethral length preservation The membranous urethra sits immediately distal to the prostatic apex and is chiefly responsible, along with its surrounding pelvic floor support structures, for urinary continence. It consists of the external rhabdosphincter which surrounds an inner layer of smooth muscle. Using pre-operative MRI, the length of membranous urethra has been shown to vary widely. A systematic review and meta-analysis has found that every extra millimetre of membranous urethral length seen on MRI pre-operatively improves early return to continence post-RP [571]. Therefore, it is likely that preservation of as much urethral length as possible during RP will maximise the chance of early return to continence. It may also be useful to measure urethral length pre-operatively to facilitate councelling of patients on their relative likelihood of early post-operative continence. 6.1.2.3.12 Cystography prior to catheter removal Cystography may be used prior to catheter removal to check for a substantial anastomotic leak. If such a leak is found, catheter removal may then be deferred to allow further healing and sealing of the anastomosis. However, small comparative studies suggest that a cystogram to assess anastomotic leakage is not indicated as standard of care before catheter removal 8 to 10 days after surgery [572]. If a cystogram is used, men with

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LUTS, large prostates, previous TURP or bladder neck reconstruction, may benefit as these factors have been associated with leakage [573, 574]. Contrast-enhanced transrectal US is an alternative [575]. 6.1.2.3.13 Urinary catheter A urinary catheter is routinely placed during RP to enable bladder rest and drainage of urine while the vesicourethral anastomosis heals. Compared to a traditional catheter duration of around 1 week, some centres remove the transurethral catheter early (post-operative day 2–3), usually after thorough anastomosis with posterior reconstruction or in patients selected peri-operatively on the basis of anastomosis quality [576-579]. No higher complication rates were found. Although shorter catheterisation has been associated with more favourable short-term functional outcomes, no differences in long-term function were found [580]. One RCT has shown no difference in rate of UTI following indwelling catheter (IDC) removal whether prophylactic ciprofloxacin was given prior to IDC removal or not, suggesting antibiotics should not be given at catheter removal [581]. As an alternative to transurethral catheterisation, suprapubic catheter insertion during RP has been suggested. Some reports suggest less bother regarding post-operative hygiene and pain [582-586], while others did not find any differences [587, 588]. No impact on long-term functional outcomes were seen. 6.1.2.3.14 Use of a pelvic drain A pelvic drain has traditionally been used in RP for potential drainage of urine leaking from the vesico-urethral anastomosis, blood, or lymphatic fluid when a PLND has been performed. Two RCTs in the robotic-assisted laparoscopic setting have been performed [589, 590]. Patients with urine leak at intra-operative anastomosis watertight testing were excluded. Both trials showed non-inferiority in complication rates when no drain was used. When the anastomosis is found to be watertight intra-operatively, it is reasonable to avoid inserting a pelvic drain. There is no evidence to guide usage of a pelvic drain in PLND. 6.1.2.4 Acute and chronic complications of surgery Post-operative incontinence and ED are common problems following surgery for PCa. A key consideration is whether these problems are reduced by using newer techniques such as RALP. Recent systematic reviews have documented complication rates after RALP [500, 591-594], and can be compared with contemporaneous reports after radical RRP [595]. Recently, a prospective controlled non-RCT of patients undergoing RP in 14 centres using RALP or RRP was published [596]. At 12 months after RALP, 21.3% of patients were incontinent, as were 20.2% after RRP. The adjusted OR was 1.08 (95% CI: 0.87–1.34). Erectile dysfunction was observed in 70.4% after RALP and 74.7% after RRP. The adjusted OR was 0.81 (95% CI: 0.66–0.98) [596]. A RCT comparing RALP and RRP reported outcomes at 12 weeks in 326 patients and functional outcomes at 2 years [494]. Urinary function scores did not differ significantly between RRP vs. RALP at 6 and 12 weeks post-surgery (74–50 vs. 71–10, p = 0.09; 83–80 vs. 82–50, p = 0.48), with comparable outcomes for sexual function scores (30–70 vs. 32–70, p = 0.45; 35–00 vs. 38–90, p = 0.18). In the RRP group 14 (9%) patients had post-operative complications vs. 6 (4%) in the RALP group. The intra-and peri-operative complications of retropubic RP and RALP are listed in Table 6.1.5. The early use of phosphodiesterase-5 (PDE5) inhibitors in penile rehabilitation remains controversial resulting in a lack of clear recommendations (see Section 8.3.2). 6.1.2.4.1 Effect of anterior and posterior reconstruction on continence Preservation of integrity of the external urethral sphincter is critical for continence post-RP. Less clear is the effect of reconstruction of surrounding support structures to return to continence. Several small RCTs have been conducted, however, pooling analyses is hampered by variation in the definitions of incontinence and surgical approach, such as open vs. robotic and intraperitoneal vs. extraperitoneal. In addition, techniques used to perform both anterior suspension or reconstruction and posterior reconstruction are varied. For example, anterior suspension is performed either through periosteum of the pubis or the combination of ligated DVC and puboprostatic ligaments (PPL). Posterior reconstruction from rhabdosphincter is described to either Denonvilliers fascia posterior to bladder or to posterior bladder wall itself. Two trials assessing posterior reconstruction in RALRP found no significant improvement in return to continence [597, 598]. A third trial using posterior bladder wall for reconstruction showed only an earlier return to 1 pad per day (median 18 vs. 30 days, p = 0.024) [599]. When combining both anterior and posterior reconstruction, where for anterior reconstruction the PPL were sutured to the anterior bladder neck, another RCT found no improvement compared to a standard anastomosis with no reconstruction [600]. Four RCTs including anterior suspension have also shown conflicting results. Anterior suspension alone through the pubic periosteum, in the setting of extraperitoneal RALRP, showed no advantage [601]. However, when combined with posterior reconstruction in RRP, one RCT showed significant improvement in return to continence at one month (7.1% vs. 26.5%, p = 0.047) and 3 months (15.4% vs. 45.2%, p = 0.016), but not

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at 6 months (57.9% vs. 65.4%, p = 0.609) [602]. Another anterior plus posterior reconstruction RCT using the Advanced Reconstruction of VesicoUrethral Support (ARVUS) technique and the strict definition of continence of ‘no pads‘, showed statistically significant improvement in continence at 2 weeks (43.8% vs. 11.8%), 4 weeks (62.5% vs. 14.7%), 8 weeks (68.8% vs. 20.6%), 6 months (75% vs. 44.1%) and 12 months (86.7% vs. 61.3%), when compared to standard posterior Rocco reconstruction [603]. Anterior suspension alone through the DVC and PPL combined without posterior construction in the setting of RRP has shown improvement in continence at one month (20% vs. 53%, p = 0.029), 3 months (47% vs. 73%, p = 0.034) and 6 months (83% vs. 100%, p = 0.02), but not at 12 months (97% vs. 100%, p = 0.313) [604]. Together, these results suggest a possible earlier return to continence, but no long-term difference. As there is conflicting evidence on the effect of anterior and/or posterior reconstruction on return to continence post-RP, no recommendations can be made. However, no studies showed an increase in adverse oncologic outcome or complications with reconstruction. 6.1.2.4.2 Deep venous thrombosis prophylaxis For EAU Guidelines recommendations on post-RP deep venous thrombosis prophylaxis, please see the Thromboprophylaxis Guidelines Section 3.1.6 [605]. However these recommendations should be adapted based on national recommendations, when available. Table 6.1.5: Intra-and peri-operative complications of retropubic RP and RALP (Adapted from [500]) Predicted probability of event Bladder neck contracture Anastomotic leak Infection Organ injury Ileus Deep-vein thrombosis Predicted rates of event Clavien I Clavien II Clavien IIIa Clavien IIIb Clavien Iva Clavien V

RALP (%) 1.0 1.0 0.8 0.4 1.1 0.6 RALP (%) 2.1 3.9 0.5 0.9 0.6 < 0.1

Laparoscopic RP (%) 2.1 4.4 1.1 2.9 2.4 0.2 Laparoscopic RP (%) 4.1 7.2 2.3 3.6 0.8 0.2

RRP (%) 4.9 3.3 4.8 0.8 0.3 1.4 RRP (%) 4.2 17.5 1.8 2.5 2.1 0.2

RALP = robot-assisted laparoscopic prostatectomy; RP = radical prostatectomy; RRP = radical retropubic prostatectomy.

6.1.2.4.3 Early complications of extended lymph node dissection Pelvic eLND increases morbidity in the treatment of PCa [512]. Overall complication rates of 19.8% vs. 8.2% were noted for eLND vs. limited LND, respectively, with lymphoceles (10.3% vs. 4.6%) being the most common adverse event. Other authors have reported more acceptable complication rates [606]. Similar rates of lymphoceles have been observed in RALP series; however, in one subgroup analysis lymphoceles were more common with the extraperitoneal approach (19%) vs. the transperitoneal approach (0%) [607, 608]. Briganti et al. [609] also showed more complications after extended compared to limited LND. Twenty percent of men suffer a complication of some sort after eLND. Thromboembolic events occur in less than 1% of cases. 6.1.3 Radiotherapy Intensity-modulated radiotherapy (IMRT) with image-guided radiotherapy (IGRT) is currently widely recognised as the best available approach for EBRT. 6.1.3.1 External beam radiation therapy 6.1.3.1.1 Technical aspects: intensity-modulated external-beam radiotherapy and volumetric arc external-beam radiotherapy Intensity-modulated external-beam radiotherapy and volumetric arc external-beam radiotherapy (VMAT) employ dynamic multileaf collimators, which automatically and continuously adapt to the contours of the target volume seen by each beam. Viani et al., show significantly reduced acute and late grade > 2 GU and GI toxicity in favour of IMRT, while BCR-free rates did not differ significantly when comparing IMRT with three-dimensional

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conformal radiation therapy (3D-CRT) in a RCT including 215 patients [610]. A meta-analysis by Yu et al., (23 studies, 9,556 patients) concluded that IMRT significantly decreases the occurrence of grade 2–4 acute GI toxicity, late GI toxicity and late rectal bleeding, and achieves better PSA relapse-free survival in comparison with 3D-CRT. Intensity-modulated external-beam radiotherapy and 3D-CRT show comparable acute rectal toxicity, late GU toxicity and OS, while IMRT slightly increases the morbidity of acute GU toxicity [611]. Wortel et al., concluded that, as compared to 3D-CRT, image-guided IMRT was associated with significantly reduced late GI toxicity whereas GU toxicities remained comparable (242 IMRT patients vs. 189 3D-CRT patients) [612]. Finally, Zapatero et al., found, based on 733 consecutive patients (295 IMRT vs. 438 3D-CRT), that compared with 3D-CRT, high-dose IMRT/IGRT is associated with a lower rate of late urinary complications despite a higher radiation dose [613]. In conclusion, IMRT plus IGRT remain the standard of care for the treatment of PCa. The advantage of VMAT over IMRT is shorter treatment times, generally two to three minutes. Both techniques allow for a more complex distribution of the dose to be delivered and provide concave isodose curves, which are particularly useful as a means of sparing the rectum. Radiotherapy treatment planning for IMRT and VMAT differs from that used in conventional EBRT, requiring a computer system capable of ‘inverse planning’ and the appropriate physics expertise. Treatment plans must conform to pre-specified dose constraints to critical organs at risk of normal tissue damage and a formal quality assurance process should be routine. With dose escalation using IMRT/VMAT organ movement becomes a critical issue in terms of both tumour control and treatment toxicity. Techniques will therefore combine IMRT/VMAT with some form of IGRT in which organ movement can be visualised and corrected for in real time, although the optimum means of achieving this is still unclear [614]. Tomotherapy is another technique for the delivery of IMRT, using a linear accelerator mounted on a ring gantry that rotates as the patient is delivered through the centre of the ring, analogous to spiral CT scanning. 6.1.3.1.2 Dose escalation Local control is a critical issue for the outcome of radiotherapy of PCa. It has been shown that local failure due to insufficient total dose is prognostic for death from PCa as a second wave of metastases is seen later on [615]. Several RCTs have shown that dose escalation (range 74–80 Gy) has a significant impact on 10-year biochemical relapse as well as metastases and disease-specific mortality [616-623]. These trials have generally included patients from several risk groups, and the use of neoadjuvant/adjuvant HT has varied (see Table 6.1.6). The best evidence of an OS benefit in patients with intermediate- or high-risk PCa, but not with low-risk PCa, derives from a non-randomised but well conducted propensity-matched retrospective analysis of the U.S. National Cancer Database including a total of 42,481 patients [624]. In everyday practice, a minimum dose of > 74 Gy is recommended for EBRT plus HT, with no different recommendations according to the patient’s risk group. If IMRT and IGRT are used for dose escalation, rates of severe late side effects (> grade 3) for the rectum are 2–3% and for the GU tract 2–5% [618, 621, 625-638]. Table 6.1.6: Randomised trials of dose escalation in localised PCa Trial

n

PCa condition

MD Anderson study 2011 [623]

301

T1-T3, N0, M0, PSA 10 ng/mL vs. PSA > 10 ng/mL

60

Radiotherapy Dose 70 vs.78 Gy

Follow-up Outcome (median) 15 yr. DM, DSM, FFF

Results All patients: 18.9% FFF at 70 Gy 12% FFF at 78 Gy (p = 0.042) 3.4% DM at 70 Gy 1.1% DM at 78 Gy (p = 0.018) 6.2% DSM at 70 Gy 3.2% DSM at 78 Gy (p = 0.043) No difference in OS (p > 0.05)

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70.2 vs.79.2 Gy 8.9 yr. including proton boost 19.8 vs. 28.8 Gy

PROG 95-09 2010 [617]

393

T1b-T2b PSA 15 ng/mL 75%

MRC RT01 2014 [622]

843

T1b-T3a, N0, M0 64 vs. 74 Gy PSA  2 acute GI 12% vs. 10%, p = 0.38 Grade > 2 acute GU 27% vs. 23%, p = 0.16

FFS = failure-free survival; FU = follow-up; fx = number fractions; GI = gastrointestinal toxicity; GU = genitourinary toxicity; mo. = months; n = number of patients; TD = total dose; SBRT = stereotactic body radiotherapy; w = weeks, yr. = years. 6.1.3.1.4 Neoadjuvant or adjuvant hormone therapy plus radiotherapy The combination of RT with LHRH ADT has definitively proven its superiority compared with RT alone followed by deferred ADT on relapse, as shown by phase III RCTs [660-664] (Table 6.1.9). The main message is that for intermediate-risk disease a short duration of around 6 months is optimal while a longer one, around 3 years, is needed for high-risk patients. A meta-analysis based on individual patient data from two RCTs (RTOG 9413 and Ottawa 0101) has compared neoadjuvant/concomitant vs. adjuvant ADT in conjunction with prostate RT and reported superior PFS with adjuvant ADT [665]. This is an important observation, which should influence future clinical trial design and evaluation of outcomes. However, there are differences between the two trials in patient characteristics, exact scheduling of neoadjuvant +/- concomitant ADT, hormonal preparation, and RT schedule. At present, either neoadjuvant or adjuvant ADT remain acceptable options for patients requiring short-term ADT in conjunction with EBRT. Table 6.1.9: Selected studies of use and duration of ADT in combination with RT for PCa Trial TNM stage RTOG 85-31 T3 or N1 M0 2005 [661]

RTOG 94-13 T1c-4 N0-1 2007 [666] M0

RTOG 86-10 T2-4 N0-1 2008 [662]

D’Amico AV, T2 N0 M0 (localised et al. 2008 unfavourable [663] risk)

n 977

Effect on OS Significant benefit for combined treatment (p = 0.002) seems to be mostly caused by patients with ISUP grade 2-5 Whole pelvic No significant difference 1,292 ADT timing 2 mo. between neoadjuvant RT vs. comparison neoadjuvant plus concomitant vs. prostate plus concomitant vs. only; 70.2 Gy adjuvant androgen suppression therapy 4 mo. adjuvant groups (interaction suppression suspected) 456 EBRT ± ADT Goserelin plus 65-70 Gy RT No significant difference at 10 yr. flutamide 2 mo. before, plus concomitant therapy Significant benefit (HR: 206 EBRT ± ADT LHRH agonist 70 Gy 0·55, 95% CI: 0.34-0.90, plus flutamide 3D-CRT p = 0.01) that may for 6 mo. pertain only to men with no or minimal co-morbidity

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Trial ADT RT EBRT ± ADT Orchiectomy or 65-70 Gy LHRH agonist 15% RP

63

RTOG 92-02 T2c-4 N0-1 2008 [667] M0

1554

Short vs. prolonged ADT

LHRH agonist given for 2 yr. as adjuvant after 4 mo. as neoadjuvant

65-70 Gy

T1c-2ab N1 EORTC 22961 2009 M0, T2c-4 N0-1 M0 [668]

970

Short vs. prolonged ADT

LHRH agonist for 6 mo. vs. 3 yr.

70 Gy 3D-CRT

415 T1-2 poorly EORTC 22863 2010 differentiated and M0, or [660] T3-4 N0-1 M0 TROG 96-01 2011 [664]

T2b-4 N0 M0

RTOG 99-10 intermediate 2015 [669] risk 94% T1-T2, 6% T3-4

802

EBRT ± ADT LHRH agonist for 3 yr. (adjuvant)

70 Gy RT

Neoadjuvant Goserelin plus flutamide ADT 3 or 6 mo. Duration before, plus concomitant suppression

66 Gy 3D-CRT

1,579 Short vs. prolonged ADT

LHRH agonist 70.2 Gy 8 + 8 vs. 8 + 28 2D/3D wk.

p = 0.73, p = 0.36 overall; significant benefit (p = 0.044) (p = 0.0061) in subset with ISUP grade 4-5 Better result with 3 yr. treatment than with 6 mo. (3.8% improvement in survival at 5 yr.) Significant benefit at 10 yr. for combined treatment (HR: 0.60, 95% CI: 0.45-0.80, p = 0.0004). No significant difference in OS reported; benefit in PCa-specific survival (HR: 0.56, 95% CI: 0.32-0.98, p = 0.04) (10 yr.: HR: 0.84, 0.65-1.08, p = 0.18) 67 vs. 68%, p = 0.62, confirms 8 + 8 wk. LHRH as a standard

ADT = androgen deprivation therapy; CI = confidence interval; EBRT = external beam radiotherapy in standard fractionation; HR = hazard ratio; LHRH = luteinising hormone-releasing hormone; mo. = months; n = number of patients; OS = overall survival; RP = radical prostatectomy; RT = radiotherapy; wk = week; yr. = year. The question of the added value of EBRT combined with ADT has been clarified with 3 RCTs. All showed a clear benefit of adding EBRT to long-term ADT (see Table 6.1.10). Table 6.1.10: Selected studies of ADT in combination with, or without, RT for PCa Trial SPCG-7/ SFUO-3 2016 [670]

TNM stage T1b-2 WHO Grade 1-3, T3 N0 M0

n 875

Trial design ADT ADT ± EBRT LHRH agonist for 3 mo. plus continuous flutamide

RT 70 Gy 3D-CRT vs. no RT

Effect on OS 34% (95% CI: 29-39%) vs. 17% (95% CI: 13-22% CSM at 12 (15) yr. favouring combined treatment (p < 0.0001 for 15-yr. results) NCIC CTG PR.3/MRC 1,205 ADT ± EBRT Continuous 65-70 Gy 10-yr. OS = 49% vs. 55% PRO7/NCIC T3-4 (88%), LHRH agonist 3D-CRT favouring combined 2011 [671] PSA > 20 ng/mL vs. no RT treatment HR: 0.7, and 2015 (64%), ISUP [672] p < 0.001) grade 4-5 (36%) N0 M0 Significant reduction of Sargos, et al. T3-4 N0 M0 273 ADT ± EBRT LHRH agonist 70 Gy 2020 [673] for 3 yr. 3D-CRT clinical progression; 5-yr. vs. no RT OS 71.4% vs. 71.5%

ADT = androgen deprivation therapy; CSM = cancer-specific mortality; EBRT = external beam radiotherapy; HR = hazard ratio; LHRH = luteinising hormone-releasing hormone; mo. = months; n = number of patients; OS = overall survival; RT = radiotherapy; 3D-CRT = three-dimensional conformal radiotherapy. 6.1.3.1.5 Combined dose-escalated radiotherapy and androgen-deprivation therapy Zelefsky et al., reported a retrospective analysis comprising 571 patients with low-risk PCa; 1,074 with intermediate-risk PCa and 906 with high-risk PCa. Three-dimensional conformal RT or IMRT were administered [674]. The prostate dose ranged from 64.8 to 86.4 Gy; doses beyond 81 Gy were delivered during the last

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10 years of the study using image-guided IMRT. Complete androgen blockade was administered at the discretion of the treating physician to 623 high-risk (69%), 456 intermediate-risk (42%) and 170 low-risk (30%) PCa patients. The duration of ADT was 3 months for low-risk patients and 6 months for intermediate-risk and high-risk patients, starting at 3 months before RT. The 10-year biochemical disease-free rate was significantly improved by dose escalation: above 75.6 Gy in low-risk, and above 81 Gy for the intermediate- and highrisk groups. It was also improved by adding 6 months of ADT in intermediate- and high-risk patients. In the multivariate analysis, neither the dose > 81 Gy, nor adding ADT, influenced OS. Three RCTs have shown that the benefits of ADT are independent of dose escalation, and that the use of ADT would not compensate for a lower radiotherapy dose: 1. The GICOR study shows a better biochemical DFS in high-risk patients for 3D-CRT radiation dose > 72 Gy when combined with long-term ADT [630]. 2. DART01/05 GICOR shows improved biochemical control and OS in high-risk patients if 2 years of adjuvant ADT is combined with high-dose RT [675]. 3. EORTC trial 22991 shows that 6 months ADT improves biochemical and clinical DFS irrespective of the dose (70, 74, 78 Gy) in intermediate-risk and low-volume high-risk localised PCa patients [676]. 6.1.3.2 Proton beam therapy In theory, proton beams are an attractive alternative to photon-beam RT for PCa, as they deposit almost all their radiation dose at the end of the particle’s path in tissue (the Bragg peak), in contrast to photons which deposit radiation along their path. There is also a very sharp fall-off for proton beams beyond their deposition depth, meaning that critical normal tissues beyond this depth could be effectively spared. In contrast, photon beams continue to deposit energy until they leave the body, including an exit dose. One RCT on dose escalation (70.2 vs. 79.2 Gy) has incorporated protons for the boost doses of either 19.8 or 28.8 Gy. This trial shows improved outcome with the higher dose but it cannot be used as evidence for the superiority of proton therapy [617]. Thus, unequivocal information showing an advantage of protons over IMRT photon therapy is still not available. Studies from the SEER database and from Harvard describing toxicity and patient-reported outcomes do not point to an inherent superiority for protons [677, 678]. In terms of longer-term GI toxicity, proton therapy might even be inferior to IMRT [678]. A RCT comparing equivalent doses of proton-beam therapy with IMRT is underway. Meanwhile, proton therapy must be regarded as an experimental alternative to photon-beam therapy. 6.1.3.3 Spacer during external beam radiation therapy Biodegradable spacer insertion involves using a liquid gel or balloon to increase the distance between the prostate and rectum and consequently reduce the amount of radiation reaching the rectum. Various materials have been used with most evidence available for CE-marked hydrogel spacers [679]. A meta-analysis including one RCT and six cohort studies using the hydrogel spacer demonstrated a 5–8% reduction in the rectal volume receiving high-dose radiation, although heterogeneity between studies is found [680]. In the final analysis of the RCT with a median follow-up of 37 months and with approximately two-thirds of patients evaluable, those treated with spacer in situ had no deterioration from baseline bowel function whilst those treated without spacer had a lower mean bowel summary score of 5.8 points which met the threshold for minimally important difference of 4–6 points [681]. This meta-analysis highlights inconsistent reporting of procedural complications. In addition, with more widespread clinical use safety reports describe uncommon, but severe and life changing, complications including prostatic abscess, fistulae and sepsis [682]. Implantation is associated with a learning curve and should only be undertaken by teams with experience of TRUS and transperineal procedures with robust audit reporting in place [683]. Its role in the context of moderate or extreme hypofractionation is as yet unclear. 6.1.3.4 Brachytherapy 6.1.3.4.1 Low-dose rate (LDR) brachytherapy Low-dose rate brachytherapy uses radioactive seeds permanently implanted into the prostate. There is a consensus on the group of patients with the best outcomes after LDR monotherapy [684]: Stage cT1b-T2a N0, M0; ISUP grade 1 with < 50% of biopsy cores involved with cancer or ISUP grade 2 with < 33% of biopsy cores involved with cancer; an initial PSA level of < 10 ng/mL; an International Prostatic Symptom Score (IPSS) < 12 and maximal flow rate > 15 mL/min on urinary flow tests [685]. In addition, with due attention to dose distribution, patients having had a previous TURP can undergo brachytherapy without an increase in risk of urinary toxicity. A minimal channel TURP is recommended and there should be at least a 3-month interval between TURP and brachytherapy to allow for adequate healing [686-689]. The only available RCT comparing RP and brachytherapy as monotherapy was closed due to poor accrual [690]. Outcome data are available from a number of large population cohorts with mature follow-up [691-698].

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The biochemical DFS for ISUP grade 1 patients after 5 and 10 years has been reported to range from 71% to 93% and 65% to 85%, respectively [691-698]. A significant correlation has been shown between the implanted dose and biochemical control [699]. A D90 (dose covering 90% of the prostate volume) of > 140 Gy leads to a significantly higher biochemical control rate (PSA < 1.0 ng/mL) after 4 years (92 vs. 68%). There is no benefit in adding neoadjuvant or adjuvant ADT to LDR monotherapy [691]. Low-dose rate brachytherapy can be combined with EBRT in good-, intermediate- and high-risk patients (see Section 6.2.3.2.3). 6.1.3.4.2 High-dose rate brachytherapy High-dose rate (HDR) brachytherapy uses a radioactive source temporarily introduced into the prostate to deliver radiation. The technical differences are outlined in Table 6.1.11. The use of the GEC (Groupe Européen de Curiethérapie)/ESTRO Guidelines is strongly recommended [700]. High-dose rate brachytherapy can be delivered in single or multiple fractions and is often combined with EBRT of at least 45 Gy [701]. A single RCT of EBRT (55 Gy in 20 fractions) vs. EBRT (35.75 Gy in 13 fractions), followed by HDR brachytherapy (17 Gy in two fractions over 24 hours) has been reported [702]. In 218 patients with organ-confined PCa the combination of EBRT and HDR brachytherapy showed a significant improvement in the biochemical disease-free rate (p = 0.04) at 5 and 10 year (75% and 46% compared to 61% and 39%). However, a very high, uncommon, rate of early recurrences was observed in the EBRT arm alone, even after 2 years, possibly due to a dose lower than the current standard used [702]. A systematic review of non-RCTs has suggested outcomes with EBRT plus HDR brachytherapy are superior to brachytherapy alone, but this needs confirmation in a prospective RCT [703]. Fractionated HDR brachytherapy as monotherapy can be offered to patients with low- and intermediate-risk PCa, who should be informed that results are only available from limited series in very experienced centres [704, 705]. Five-year PSA control rates over 90% are reported, with late grade 3+ GU toxicity rates < 5% and no, or very minimal, grade 3+ GI toxicity rates [704, 705]. Table 6.1.11: Difference between LDR and HDR brachytherapy

Low dose rate (LDR)

High dose rate (HDR)

Differences in prostate brachytherapy techniques • Permanent seeds implanted • Uses Iodine-125 (I-125) (most common), Palladium-103 (Pd-103) or Cesium-131 isotopes • Radiation dose delivered over weeks and months • Acute side effects resolve over months • Radiation protection issues for patient and carers • Temporary implantation • Iridium-192 (IR-192) isotope introduced through implanted needles or catheters • Radiation dose delivered in minutes • Acute side effects resolve over weeks • No radiation protection issues for patient or carers

6.1.3.5 Acute side effects of external beam radiotherapy and brachytherapy Gastrointestinal and urinary side effects are common during and after EBRT. In the EORTC 22991 trial, approximately 50% of patients reported acute GU toxicity of grade 1, 20% of grade 2, and 2% grade 3. In the same trial, approximately 30% of patients reported acute grade 1 GI toxicity, 10% grade 2, and less than 1% grade 3. Common toxicities included dysuria, urinary frequency, urinary retention, haematuria, diarrhoea, rectal bleeding and proctitis [629]. In addition, general side effects such as fatigue are common. It should be noted that the incidence of acute side effects is greater than that of late effects (see Section 8.2.2.1), implying that most acute effects resolve. In a RCT of conventional dose EBRT vs. EBRT and LDR brachytherapy the incidence of acute proctitis was reduced in the brachytherapy arm, but other acute toxicities were equivalent [706]. Acute toxicity of HDR brachytherapy has not been documented in a RCT, but retrospective reports confirm lower rates of GI toxicity compared with EBRT alone and grade 3 GU toxicity in 10%, or fewer, patients, but a higher incidence of urinary retention [707]. Similar findings are reported using HFX; in a pooled analysis of 864 patients treated using extreme HFX and stereotactic radiotherapy, declines in urinary and bowel domains were noted at 3 months which returned to baseline, or better, by 6 months [708].

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6.1.4 Hormonal therapy 6.1.4.1 Introduction 6.1.4.1.1 Different types of hormonal therapy Androgen deprivation can be achieved by either suppressing the secretion of testicular androgens or inhibiting the action of circulating androgens at the level of their receptor. These two methods can be combined to achieve what has been known as complete (or maximal or total) androgen blockade (CAB) using the oldfashioned anti-androgens [709]. 6.1.4.1.1.1 Testosterone-lowering therapy (castration) 6.1.4.1.1.1.1 Castration level The castration level is < 50 ng/dL (1.7 nmol/L), which was defined more than 40 years ago when testosterone testing was less sensitive. Current methods have shown that the mean value after surgical castration is 15 ng/dL [710]. Therefore, a more appropriate level should be defined as < 20 ng/dL (1 nmol/L). This definition is important as better results are repeatedly observed with lower testosterone levels compared to 50 ng/dL [711-713]. However, the castrate level considered by the regulatory authorities and in clinical trials addressing castration in PCa is still the historical < 50 ng/dL (1.7 mmol/L). 6.1.4.1.1.1.2 Bilateral orchiectomy Bilateral orchiectomy or subcapsular pulpectomy is still considered the primary treatment modality for ADT. It is a simple, cheap and virtually complication-free surgical procedure. It is easily performed under local anaesthesia and it is the quickest way to achieve a castration level which is usually reached within less than twelve hours. It is irreversible and therefore does not allow for intermittent treatment [714]. 6.1.4.1.1.1.3 Oestrogens Treatment with oestrogens results in testosterone suppression and is not associated with bone loss [715]. Early studies tested oral diethylstilboestrol (DES) at several doses. Due to severe side effects, especially thromboembolic complications, even at lower doses these drugs are not considered as standard first-line treatment [716-718]. 6.1.4.1.1.1.4 Luteinising-hormone-releasing hormone agonists Long-acting LHRH agonists are currently the main forms of ADT. These synthetic analogues of LHRH are delivered as depot injections on a 1-, 2-, 3-, 6-monthly, or yearly, basis. The first injection induces a transient rise in luteinising hormone (LH) and follicle-stimulating hormone (FSH) leading to the ‘testosterone surge’ or ‘flare-up’ phenomenon which starts two to three days after administration and lasts for about one week. This may lead to detrimental clinical effects (the clinical flare) such as increased bone pain, acute bladder outlet obstruction, obstructive renal failure, spinal cord compression, and cardiovascular death due to hypercoagulation status [719]. Patients at risk are usually those with high-volume symptomatic bony disease. Concomitant therapy with an anti-androgen decreases the incidence of clinical flare but does not completely remove the risk. Anti-androgen therapy is usually continued for 4 weeks but neither the timing nor the duration of anti-androgen therapy are based on strong evidence. In addition, the long-term impact of preventing ‘flareup’ is unknown [720, 721]. Chronic exposure to LHRH agonists results in the down-regulation of LHRH-receptors, suppressing LH and FSH secretion and therefore testosterone production. A castration level is usually obtained within 2 to 4 weeks [722]. Although there is no formal direct comparison between the various compounds, they are considered to be equally effective [723]. No survival difference with orchiectomy has been reported despite the lack of high-quality trials [724]. The different products have practical differences that need to be considered in everyday practice, including the storage temperature, whether a drug is ready for immediate use or requires reconstitution, and whether a drug is given by subcutaneous or intramuscular injection. 6.1.4.1.1.1.5 Luteinising-hormone-releasing hormone antagonists Luteinising-hormone releasing hormone antagonists immediately bind to LHRH receptors, leading to a rapid decrease in LH, FSH and testosterone levels without any flare. The practical shortcoming of these compounds is the lack of a long-acting depot formulation with, so far, only monthly formulations being available. Degarelix is a LHRH antagonist. The standard dosage is 240 mg in the first month followed by monthly injections of 80 mg. Most patients achieve a castrate level at day three [722]. A phase III RCT compared degarelix to monthly leuprorelin following up patients for 12 months, suggesting a better PSA PFS for degarelix 240/80 mg compared to monthly leuprorelin [725]. A systematic review did not show a major difference between agonists and degarelix and highlighted the paucity of on-treatment data beyond 12 months as well as the lack of survival data [726]. Its definitive superiority over the LHRH analogues remains to be proven.

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Relugolix is an oral gonadotropin-releasing hormone antagonist. It was compared to the LHRH agonist leuprolid in a randomised phase III trial [727]. The primary endpoint was sustained testosterone suppression to castrate levels through 48 weeks. There was a significant difference of 7.9 percentage points (95% CI: 4.1–11.8) showing non-inferiority and superiority of relugolix. The incidence of major adverse cardiovascular events was significantly lower with relugolix (prespecified safety analysis). Relugolix has been approved by the FDA [728]. 6.1.4.1.1.1.6 Anti-androgens These oral compounds are classified according to their chemical structure as: • steroidal, e.g., cyproterone acetate (CPA), megestrol acetate and medroxyprogesterone acetate; • non-steroidal or pure, e.g., nilutamide, flutamide and bicalutamide. Both classes compete with androgens at the receptor level. This leads to an unchanged or slightly elevated testosterone level. Conversely, steroidal anti-androgens have progestational properties leading to central inhibition by crossing the blood-brain barrier. 6.1.4.1.1.1.6.1 Steroidal anti-androgens These compounds are synthetic derivatives of hydroxyprogesterone. Their main pharmacological side effects are secondary to castration (gynaecomastia is quite rare) whilst the non-pharmacological side effects are cardiovascular toxicity (4–40% for CPA) and hepatotoxicity. Cyproterone acetate was the first licensed anti-androgen but the least studied. Its most effective dose as monotherapy is still unknown. Although CPA has a relatively long half-life (31–41 hours), it is usually administered in two or three fractionated doses of 100 mg each. In one RCT CPA showed a poorer OS when compared with LHRH analogues [729]. An underpowered RCT comparing CPA monotherapy with flutamide in M1b PCa did not show any difference in DSS and OS at a median follow-up of 8.6 years [730]. Other CPA monotherapy studies suffer from methodological limitations preventing firm conclusions. 6.1.4.1.1.1.6.2 Non-steroidal anti-androgens Non-steroidal anti-androgen monotherapy with e.g., nilutamide, flutamide or bicalutamide does not suppress testosterone secretion and it is claimed that libido, overall physical performance and bone mineral density (BMD) are frequently preserved [731]. Non-androgen-related pharmacological side effects differ between agents. Bicalutamide shows a more favourable safety and tolerability profile than flutamide and nilutamide [732]. The dosage licensed for use in CAB is 50 mg/day, and 150 mg for monotherapy. The androgen pharmacological side effects are mainly gynaecomastia (70%) and breast pain (68%). However, non-steroidal anti-androgen monotherapy offers clear bone protection compared with LHRH analogues and probably LHRH antagonists [731, 733]. All three agents share the potential for liver toxicity (occasionally fatal), requiring regular monitoring of patients’ liver enzymes. 6.1.4.1.1.2 New androgen receptor pathway targetting agents (ARTA) Once on ADT the development of castration-resistance (CRPC) is only a matter of time. It is considered to be mediated through two main overlapping mechanisms: androgen-receptor (AR)-independent and AR-dependent mechanisms (see Section 6.5 - Castrate-resistant PCa). In CRPC, the intracellular androgen level is increased compared to androgen sensitive cells and an over-expression of the AR has been observed, suggesting an adaptive mechanism [734]. This has led to the development of several new compounds targeting the androgen axis. In mCRPC, abiraterone acetate plus prednisolone and enzalutamide have been approved. In addition to ADT (sustained castration), abiraterone acetate plus prednisolone, apalutamide and enzalutamide have been approved for the treatment of metastatic hormone sensitive PCa (mHSPC) by the FDA, abiraterone/ prednisolone and apalutamide also by the EMA (Note: EMA issued a positive opinion to extend the indication for enzalutamide at the time of this publication, final approval is pending). For the updated approval status see EMA and FDA websites [735-739]. Finally, apalutamide, darolutamide and enzalutamide have been approved for non-metastatic CRPC (nmCRPC) at high risk of further metastases [740-744]. 6.1.4.1.1.2.1 Abiraterone acetate Abiraterone acetate is a CYP17 inhibitor (a combination of 17α-hydrolase and 17,20-lyase inhibition). By blocking CYP17, abiraterone acetate significantly decreases the intracellular testosterone level by suppressing its synthesis at the adrenal level and inside the cancer cells (intracrine mechanism). This compound must be used together with prednisone/prednisolone to prevent drug-induced hyperaldosteronism [735]. 6.1.4.1.1.2.2 Apalutamide, darolutamide, enzalutamide (alphabetical order) These agents are novel non-steroidal anti-androgens with a higher affinity for the AR receptor than

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bicalutamide. While previous non-steroidal anti-androgens still allow transfer of ARs to the nucleus and would act as partial agonists, all three agents also block AR transfer and therefore suppress any possible agonist-like activity [739-741]. Darolutamide has structurally unique properties [740]. In particular, in preclinical studies, it showed not to cross the blood-brain barrier [745, 746]. 6.1.4.1.1.3 New compounds 6.1.4.1.1.3.1 PARP inhibitors Poly (ADP-ribose) polymerase inhibitors (PARPi) block the enzyme poly ADP ribose polymerase (PARP) and were developed aiming to selectively target cancer cells harbouring BRCA mutations and other mutations inducing homologous recombination deficiency and high level of replication pressure with a sensitivity to PARPi treatment. Due to the oncogenic loss of some DNA repair effectors and incomplete DNA repair repertoire, some cancer cells are addicted to certain DNA repair pathways such as Poly (ADP-ribose) polymerase (PARP)-related single-strand break repair pathway. The interaction between BRCA and PARP is a form of synthetic lethal effect which means the simultaneously functional loss of two genes lead to cell death, while a defect in any single gene only has a limited effect on cell viability [747]. The therapeutic indication for PCa is discussed in Section 6.5.8.1. 6.1.4.1.1.3.2 Immune checkpoint inhibitors Immune checkpoints are key regulators of the immune system. Checkpoint proteins, such as B7-1/B7-2 on antigen-presenting cells (APC) and CTLA-4 on T cells, help keep the immune responses in an equilibrium. The binding of B7-1/B7-2 to CTLA-4 keeps the T cells in the inactive state while blocking the binding of B7-1/B7-2 to CTLA-4 whilst an immune checkpoint inhibitor (anti-CTLA-4 antibody) allows the T cells to be active and to kill tumour cells. Approved checkpoint inhibitors target the molecules CTLA4, programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1). Programmed death-ligand 1 is the transmembrane programmed cell death 1 protein which interacts with PD-L1 (PD-1 ligand 1). Cancer-mediated upregulation of PD-L1 on the cell surface may inhibit T cells. Antibodies that bind to either PD-1 or PD-L1 and therefore block the interaction may allow the T cells to induce cell killing. Examples of PD-1 inhibitors are pembrolizumab and nivolumab; of PD-L1 inhibitors, atezolizumab, avelumab and durvalumab and an example of CTLA4 inhibitors is ipilimumab [748, 749]. Therapeutic use is discussed in Section 6.5 - Castration-resistant PCa. 6.1.4.1.1.3.3 Protein kinase B (AKT) inhibitors Aberrant activation of the PI3K (phosphatidylinositol-4,5-bisphosphate 3-kinase)/AKT pathway, predominately due to PTEN loss (phosphatase and tensin homologue deleted from chromosome 10), is common in PCa (40– 60% of mCRPC) and is associated with worse prognosis. The androgen receptor signaling and AKT pathway are reciprocally cross-regulated, so that inhibition of one leads to upregulation of the other. AKT inhibitors are small molecules which are designed to target and bind to all three isoforms of AKT, which is a key component of the PI3K/AKT pathway and a key driver of cancer cell growth. Ipatasertib is an oral, highly specific, AKT inhibitor which shows clinically significant activity when combined with abiraterone acetate in patients with loss of the tumour suppressor protein PTEN (on IHC) within the tumour [750, 751]. The therapeutic indication for PCa is discussed in Section 6.5.6.5. 6.1.5 Investigational therapies 6.1.5.1 Background Besides RP, EBRT and brachytherapy, other modalities have emerged as potential therapeutic options in patients with clinically localised PCa [752-755]. In this section, both whole gland and focal treatment will be considered, looking particularly at high-intensity focused US (HIFU), cryotherapeutic ablation of the prostate (cryotherapy) and focal photodynamic therapy, as sufficient data are available to form the basis of some initial judgements. Other options such as radiofrequency ablation and electroporation, among others, are considered to be in the early phases of evaluation [756]. In addition, a relatively newer development is focal ablative therapy [756, 757] whereby lesion-targeted ablation is undertaken in a precise organ-sparing manner. All these modalities have been developed as minimally invasive procedures with the aim of providing equivalent oncological safety, reduced toxicity, and improved functional outcomes. 6.1.5.2 Cryotherapy Cryotherapy uses freezing techniques to induce cell death by dehydration resulting in protein denaturation, direct rupture of cellular membranes by ice crystals and vascular stasis and microthrombi, resulting in stagnation of the microcirculation with consecutive ischaemic apoptosis [752-755]. Freezing of the prostate is ensured by the placement of 17 gauge cryo-needles under TRUS guidance, placement of thermosensors at the level of the external sphincter and rectal wall, and insertion of a urethral warmer. Two freeze-thaw cycles are used under TRUS guidance resulting in a temperature of -40°C in the mid-gland and at the neurovascular

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bundle. Currently, third and fourth generation cryotherapy devices are mainly used. Since its inception, cryotherapy has been used for whole-gland treatment in PCa either as a primary or salvage treatment option. The main adverse effects of cryosurgery are ED (18%), urinary incontinence (2–20%), urethral sloughing (0–38%), rectal pain and bleeding (3%) and recto-urethral fistula formation (0–6%) [758]. There is a lack of prospective comparative data regarding oncological outcomes of whole-gland cryosurgery as a curative treatment option for men with localised PCa, with most studies being non-comparative single-arm case series with short follow-up [758]. 6.1.5.3 High-intensity focused ultrasound High-intensity focused ultrasound consists of focused US waves emitted from a transducer that cause tissue damage by mechanical and thermal effects as well as by cavitation [759]. The goal of HIFU is to heat malignant tissue above 65°C so that it is destroyed by coagulative necrosis. High-intensity focused US is performed under general or spinal anaesthesia, with the patient lying in the lateral or supine position. Highintensity focused US has previously been widely used for whole-gland therapy. The major adverse effects of HIFU include acute urinary retention (10%), ED (23%), urethral stricture (8%), rectal pain or bleeding (11%), recto-urethral fistula (0–5%) and urinary incontinence (10%) [758]. Disadvantages of HIFU include difficulty in achieving complete ablation of the prostate, especially in glands larger than 40 mL, and in targeting cancers in the anterior zone of the prostate. Similar to cryosurgery, the lack of any long-term prospective comparative data on oncological outcomes prevents whole-gland HIFU from being considered as a reasonable alternative to the established curative treatment options [758]. 6.1.5.4 Focal therapy During the past two decades, there has been a trend towards earlier diagnosis of PCa as a result of greater public and professional awareness leading to the adoption of both formal and informal screening strategies. The effect of this has been that men are identified at an earlier stage with smaller tumours that occupy only 5–10% of the prostate volume, with a greater propensity for unifocal or unilateral disease [760-762]. Most focal therapies to date have been achieved with ablative technologies: cryotherapy, HIFU, photodynamic therapy, electroporation, and focal RT by brachytherapy or CyberKnife® Robotic Radiosurgery System technology (Accuray Inc., Sunnyvale, CA, USA). The main purpose of focal therapy is to ablate tumours selectively whilst limiting toxicity by sparing the neurovascular bundles, sphincter and urethra [763-765]. A systematic review and network meta-analysis [758] on ablative therapy in men with localised PCa performed a sub-group analysis of focal therapy vs. RP and EBRT. Nine case series reporting on focal therapy were identified (5 studies reporting on focal cryosurgical ablation of the prostate [CSAP], three studies on focal HIFU, and one study reported on both). For focal CSAP vs. RP or EBRT, no statistically significant differences were found for BCR at 3 years. For focal HIFU vs. RP or EBRT there were neither comparable data on oncological-, continence- nor potency outcomes at one year or more. More recently, Valerio et al., [757] performed a systematic review to summarise the evidence regarding the effectiveness of focal therapy in localised PCa. Data from 3,230 patients across 37 studies were included, covering different energy sources including HIFU, CSAP, photodynamic therapy, laser interstitial thermotherapy, focal brachytherapy, irreversible electroporation and radiofrequency ablation. The overall quality of the evidence was low, due to the majority of studies being single-centre, non-comparative and retrospective in design, heterogeneity of definitions and approaches, follow-up strategies, outcomes, and duration of follow-up. Although the review suggests that focal therapy has a favourable toxicity profile in the short-to-medium term, its oncological effectiveness remains unproven due to lack of reliable comparative data against standard interventions such as RP and EBRT. In order to update the evidence base, a systematic review incorporating a narrative synthesis was performed by the Panel, including comparative studies assessing focal ablative therapy vs. radical treatment, AS or alternative focal ablative therapy, published between 1st January 2000 to 12th June 2020 [766]. Only English language papers were included in the review. Primary outcomes included oncological outcomes, adverse events and functional outcomes. Only comparative studies recruiting at least 50 patients in every arm were included. Relevant systematic reviews and ongoing prospective comparative studies with the same PICO elements were included, and systematic reviews were quality assessed using AMSTAR criteria. The results have been reported elsewhere [766]. In brief, out of 1,119 articles identified, 4 primary studies (1 RCT and 3 retrospective cohort studies) [767-771] recruiting 3,961 patients, and 10 systematic reviews were included [758]. Only qualitative synthesis was possible due to clinical heterogeneity. Overall risk of bias (RoB) and confounding were moderate to high. Comparative effectiveness data regarding focal therapy were inconclusive. Data quality and applicability were poor due to clinical heterogeneity, RoB and confounding, lack of long-term data, inappropriate outcome measures and poor external validity. The majority of systematic reviews had a low or critically low confidence rating. The only identified RCT, Azzouzi et al., [767] deserves discussion. The authors compared focal

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therapy using padeliporfin-based vascular-targeted photodynamic therapy (PDT) vs. AS in men with very lowrisk PCa. The study found, at a median follow-up of 24 months, that less patients progressed in the PDT arm compared with the AS arm (adjusted HR: 0.34, 95% CI: 0.24–0.46), and needed less radical therapy (6% vs. 29%, p < 0.0001). In addition, more men in the PDT arm had a negative prostate biopsy at two years than men in the AS arm (adjusted RR: 3.67, 95% CI: 2.53–5.33). Updated results were published in 2018 showing that these benefits were maintained after four years [768]. Nevertheless, limitations of the study include inappropriately comparing an intervention designed to destroy cancer tissue in men with low-risk PCa against an intervention primarily aimed at avoiding unnecessary treatment in men with low-risk PCa, and an unusually high observed rate of disease progression in the AS arm (58% in two years). Furthermore, more patients in the AS arm chose to undergo radical therapy without a clinical indication which may have introduced confounding bias. Finally, the AS arm did not undergo any confirmatory biopsy or any mpMRI scanning, which is not representative of contemporary practice. Given the lack of robust comparative data on medium- to long-term oncological outcomes for focal therapy against curative interventions (i.e. RP or EBRT), significant uncertainties remain in regard to focal therapy as a proven alternative to either AS or radical therapy. Consequently, robust prospective trials reporting standardised outcomes [772] are needed before recommendations in support of focal therapy for routine clinical practice can be made [756, 772, 773]. At this time focal therapy should only be performed within the context of a clinical trial setting or well-designed prospective cohort study. 6.1.6

General guidelines for the treatment of prostate cancer

Recommendations Inform patients that based on robust current data with up to 12 years of follow-up, no active treatment modality has shown superiority over any other active management options or deferred active treatment in terms of overall- and PCa-specific survival for clinically localised disease. Offer a watchful waiting policy to asymptomatic patients with a life expectancy < 10 years (based on co-morbidities). Inform patients that all active treatments have side effects. Surgical treatment Inform patients that no surgical approach (open-, laparoscopic- or robotic radical prostatectomy) has clearly shown superiority in terms of functional or oncological results. When a lymph node dissection (LND) is deemed necessary, perform an extended LND template for optimal staging. Do not perform nerve-sparing surgery when there is a risk of ipsilateral extracapsular extension (based on cT stage, ISUP grade, nomogram, multiparametric magnetic resonance imaging). Do not offer neoadjuvant androgen deprivation therapy before surgery. Radiotherapeutic treatment Offer intensity-modulated radiation therapy (IMRT) plus image-guided radiation therapy (IGRT) for definitive treatment of PCa by external-beam radiation therapy. Offer moderate hypofractionation (HFX) with IMRT including IGRT to the prostate to patients with localised disease. Ensure that moderate HFX adheres to radiotherapy protocols from trials with equivalent outcome and toxicity, i.e. 60 Gy/20 fractions in 4 weeks or 70 Gy/28 fractions in 6 weeks. Offer low-dose rate (LDR) brachytherapy monotherapy to patients with good urinary function and low- or good prognosis intermediate-risk localised disease. Offer LDR or high-dose rate brachytherapy boost combined with IMRT including IGRT to patients with good urinary function and intermediate-risk disease with adverse features or high-risk disease. Active therapeutic options outside surgery and radiotherapy Only offer cryotherapy and high-intensity focused ultrasound within a clinical trial setting or well-designed prospective cohort study. Only offer focal therapy within a clinical trial setting or well-designed prospective cohort study.

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6.2

Treatment by disease stages

6.2.1 Treatment of low-risk disease 6.2.1.1 Active surveillance The main risk for men with low-risk disease is over treatment (see Sections 6.1.1.2 and 6.1.1.4); therefore, AS should be considered for all such patients. 6.2.1.1.1 Active surveillance - inclusion criteria Guidance regarding selection criteria for AS is limited by the lack of data from prospective RCTs. As a consequence, the Panel undertook an international collaborative study involving healthcare practitioners and patients to develop consensus statements for deferred treatment with curative intent for localised PCa, covering all domains of AS (DETECTIVE Study) [252]. The criteria most often published include: ISUP grade 1, clinical stage cT1c or cT2a, PSA < 10 ng/mL and PSA density < 0.15 ng/mL/cc [468, 774]. The latter threshold remains controversial [774, 775]. These criteria were supported by the DETECTIVE consensus. There was no agreement around the maximum number of cores that can be involved with cancer or the maximum percentage core involvement although there was recognition that cT2c disease and extensive disease on MRI should exclude men from AS. The DETECTIVE Study concluded that men with favourable ISUP 2 cancer (PSA < 10 ng/mL, clinical stage < cT2a and a low number of positive cores) should also be considered for deferred treatment [252]. In this setting, re-biopsy within 6 to 12 months to exclude sampling error is mandatory [774, 776] even if this could be modified in the future [777]. A systematic review and meta-analysis found three clinico-pathological variables which were significantly associated with reclassification, which included PSA density, > 2 positive cores, and African-American race [778]. The DETECTIVE consensus group were clear that those with ISUP 3 disease should not be considered. In addition, a previous pathology consensus group suggested excluding men from AS when any of the following features were present: predominant ductal carcinoma (including pure intraductal carcinoma), sarcomatoid carcinoma, small cell carcinoma, EPE or LVI in needle biopsy [345] and perineal invasion [779], and this view was supported. Recently, a multidisciplinary consensus conference on germline testing attempted to develop a genetic implementation framework for the management of PCa [139]. Based on consensus, BRCA2-gene testing was recommended for AS discussions. However, the nature of such discussions and how a positive result influences management were beyond the scope of the project. For now, if included in AS programmes, patients with a BRCA2 mutation should be cautiously monitored; more robust data is needed to be able to make definitive conclusions. 6.2.1.1.2 Tissue-based prognostic biomarker testing Biomarkers, including Oncotype Dx®, Prolaris®, Decipher®, PORTOS and ProMark® are promising (see 5.2.8.3). however, further data will be needed before such markers can be used in standard clinical practice [198]. 6.2.1.1.3 Imaging for treatment selection In men eligible for AS based upon systematic biopsy findings alone MRI can detect suspicious lesions triggering reclassification at confirmatory biopsy [780, 781]. However, systematic biopsy retains substantial added value at confirmatory biopsy. A meta-analysis evaluated the proportion of men eligible for AS based on systematic TRUS-guided biopsy in whom the cancer was upgraded by MRI-TBx (17%) and systematic biopsy (20%) at confirmatory biopsy [782]. Ten percent of patients were upgraded by both biopsy methods, meaning MRI-TBx upgraded an additional 7% (95% CI: 5–10%) of men, whilst systematic biopsy upgraded an additional 10% of men (95% CI: 8–14%). Even if the analysed series used different definitions for csPCa (and thus for cancer upgrading), MRITBx and systematic biopsy appear to be complementary to each other, both missing a significant proportion of cancer upgrading or reclassification. Therefore, combining the two biopsy techniques appears to be the best way to select patients for AS at confirmatory biopsy. Magnetic resonance imaging-positive men have approximately a three times higher chance (RR: 2.77, 95% CI: 1.76–4.38) to cancer upgrading than MRI-negative men, having their first MRI [782]. Similar results were obtained in an enrolled AS cohort (ISUP grade 1) which was compared to a surveillance cohort from the pre-MRI era; the MRI-negative men had an HR of 0.61 (95% CI: 0.39–0.95, p = 0.03) for upgrading, while the MRI-positive men had an HR of 1.96 (95% CI:1.36–2.82, p < 0.01) [783]. The Active Surveillance Magnetic Resonance Imaging Study (ASIST) randomised men on AS scheduled for confirmatory biopsy to either 12-core systematic biopsy or to MRI with targeted biopsy (when indicated) combined with systematic biopsy, up to 12 cores in total, avoiding oversampling in the MRI arm [784]. The initial report showed little benefit from targeted biopsy. However, after 2 years of follow-up, use of

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MRI before confirmatory biopsy resulted in fewer failures of surveillance (19% vs. 35%, p = 0.017) and in fewer patients progressing to ISUP grade > 2 cancer (9.9% vs. 23%, p = 0.048) [785]. At the DECTECTIVE consensus meeting it was agreed that men eligible for AS after combined systematic- and MRI-targeted biopsy do not require a confirmatory biopsy [252]. 6.2.1.1.4 Monitoring during active surveillance Based on the DETECTIVE consensus study, the follow-up strategy should be based on serial DRE (at least once yearly), PSA (at least once, every 6 months) and repeated biopsy [252]. Several authors have reported data on sequential MRI evaluation, summarised in a review [786]. In MRI-positive men the overall upgrading from ISUP 1 to ISUP > 2 PCa was 30% (81/269), following combined targeted and standard biopsies. Upgrading occurred in 39% of these MRI-positive patients with MRI showing progression between entry and follow-up MRI, while only 21% upgrading occurred in patients with MRI showing stable findings. These data suggest that radiological progression is a predictor for upgrading. However, in three recent studies not included in this review, an association between MRI progression and pathological upgrade was not observed [787-789]. In a retrospective single-centre study of men on AS with ISUP 1 cancer and serial MRIs, the upgrading at 1 year was 24% (29/122) [787]. On multivariable logistic regression, radiological progression between serial mpMRI examinations was not predictive of upgrading. In a prospective single-centre study of men on AS with ISUP 1 cancer and serial MRIs, the upgrading at 1 year was 32% (35/111) in the overall population and 48% (30/63) in MRI-positive men. However, no difference in upgrading was observed between MRI-positive men with radiological progression (41% [7/17], 95% CI: 18–67%) and MRI-positive men without radiological progression (50% [23/46], 95% CI: 35–65%) [788]. These results were confirmed in a single-centre retrospective analysis of 207 men with ISUP grade 1 cancer with a 3-year interval between diagnosis and follow-up, with 42% (20/48) upgrading in men with radiological progression and 31% (41/132) in men with stable disease. The authors concluded that increases in MRI score were not associated with reclassification after adjusting for the 3-year MRI score (p = 0.9) [789]. Data are more limited on serial unchanged negative MRI findings. In a small side study including 75 men within the Prostate Cancer Research International Active Surveillance (PRIAS) study with an MRI at baseline, 46 (61%) had a negative MRI. Fifteen percent (7/46) were reclassified to ISUP grade > 2 PCa at 12 months by systematic biopsy [790]. Other studies on serial negative MRI showed upgrading to ISUP grade > 2 PCa in 2% (1/56) [781], 5% (2/41) [787], 10% (5/48) [788], and 16% (8/51), respectively [789]. Data on the combination of serial MRI and PSA as a trigger for re-biopsy are even more limited. Using MRI and PSA changes as the sole triggers for re-biopsy would have detected only 70% (14/20) of progressions. Changes on MRI, prompting a non-protocol biopsy, accounted for 50% (10/20) of detected upgrading and resulted in 10 (50%) additional biopsy procedures which failed to show pathological progression [791]. Protocol-based re-biopsy, without MRI or PSA changes, however, detected pathological progression in only 7% (6/87) of men. In another serial MRI study on AS, PSA velocity was significantly associated with subsequent requirement for radical therapy in patients with no visible lesions (negative MRI); 0.98 (0.56–1.11) ng/mL/year in progressed disease vs. 0.12 (0.16 to 0.51) ng/mL/year in non-progressed disease (p < 0.01) [781]. Prostate-specific antigen doubling time was significant in patients with visible lesions (positive MRI); 3.2 (1.9–5.2) years in histopathological progressed disease vs. 5.7 (2.5–11.1) years in histopathological nonprogressed disease (p < 0.01). In patients with no visible lesions on their first MRI, a cut-off of 0.5 ng/mL/year in PSA-velocity had a sensitivity of 89% (8/9 progressions identified) and a specificity of 75% for progression to radical therapy [781]. Another study showed similar results on PSA-velocity and PSA doubling times in MRInegative men on AS [792]. For the PSA-velocity threshold value of > 0.5 ng/mL/year, sensitivity and specificity were 92% and 86%, respectively. Prostate-specific antigen doubling time < 3 years in the first 2 years were associated with tumour reclassification in 82% of cases (9/11) with a sensitivity and specificity for detection of tumour progression of 69% and 97%, respectively. The DETECTIVE consensus study concluded that repeat biopsy should be performed if there is a change in mpMRI (i.e. increase in PI-RADS score, lesion volume or radiological T stage), or by DRE or PSA progression, and if repeat biopsies are required they should be performed by MRI-guided targeted biopsies (including in-bore, cognitive guidance or MRI fusion) combined with systematic biopsies [252]. The situation regarding protocol-mandated, untriggered, biopsies or untriggered mpMRI biopsies remains less clear. The DETECTIVE study failed to achieve consensus on these issues. Most contemporary long-term single-arm case series on AS include protocol-mandated untriggered prostate biopsies at varying intervals, although comparative effectiveness data remain lacking. Presently, it remains unclear if regular repeat mpMRI should be performed in the absence of any triggers (i.e. protocol-mandated). Similarly, it remains unclear if protocol-mandated, untriggered repeat prostate biopsies should be performed at regular intervals. As such, no recommendations can be made at this time regarding these issues.

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6.2.1.1.5 Active Surveillance - when to change strategy Men may remain on AS whilst they continue to consent, have a life expectancy of > 10 years and the disease remains indolent. Patient anxiety about continued surveillance occurs in around 10% of patients on AS [793] and was recognised as a valid reason for active treatment [252]. More common is the development of other co-morbidities which may result in a decision to transfer to a WW strategy. A PSA change alone (especially a PSA-DT < 3 years) is a less powerful indicator to change management based on its weak link with grade progression [794, 795]. As a consequence, this should instead trigger further investigation. There was clear agreement in the DETECTIVE consensus meeting that a change in PSA should lead to repeat-MRI and repeat biopsy. It was also agreed that changes on follow-up MRI needed a confirmatory biopsy before considering active treatment. However, there was no agreement on the histopathology criteria (neither the extent of core involvement nor the number of cores involved) required to trigger a change in management [252]. 6.2.1.2 Alternatives to active surveillance for the treatment of low-risk disease In terms of alternatives to AS in the management of patients with low-risk disease there is some data from randomised studies. In the PIVOT trial (Section 6.1.1.3.1) which compared surgery vs. observation, only 42% of patients had low-risk disease [478]. Sub-group analysis revealed that for low-risk disease there was no statistically significant difference in all-cause mortality between surgery vs. observation (RR: 0.93, 95% CI: 0.78–1.11). In the ProtecT study (Section 6.1.1.4) which compared AM vs. surgery vs. EBRT, 56% of patients had low-risk disease [467]. However, no sub-group analysis was performed on this group. The study found no difference between the three arms in terms of OS and CSS, but AM had higher metastatic progression compared with surgery or EBRT (6.0% vs. 2.6). There is no robust data comparing contemporary AS protocols with either surgery or EBRT in patients with low-risk disease. On balance, although AS should be the default management strategy in patients with low-risk disease and a life expectancy > 10 years, it would be reasonable to consider surgery and EBRT as alternatives to AS in patients suitable for such treatments and who accept a trade-off between toxicity and prevention of disease progression. 6.2.1.3

Summary of evidence and guidelines for the treatment of low-risk disease

Summary of evidence Systematic biopsies have been scheduled in AS protocols, the number and frequency of biopsies varied, there is no approved standard. Although per-protocol MR scans are increasingly used in AS follow-up no conclusive evidence exist in terms of their benefit/and whether biopsy may be ommitted based on the imaging findings. Personalised risk-based approaches will ultimately replace protocol-based management of patients on AS.

Recommendations Active surveillance (AS) Selection of patients Offer AS to patients with a life expectancy > 10 years and low-risk disease. If a patient has had upfront multiparametric magnetic resonance imaging (mpMRI) followed by systematic and targeted biopsies there is no need for confirmatory biopsies. Patients with intraductal and cribiform histology on biopsy should be excluded from AS. Perform a mpMRI before a confirmatory biopsy if no MRI has been performed before the initial biopsy. Take both targeted biopsy (of any PI-RADS > 3 lesion) and systematic biopsy if a confirmatory biopsy is performed. Follow-up strategy Perform serum prostate-specific antigen (PSA) assessment every 6 months. Perform digital rectal examination (DRE) every 12 months. Counsel patients about the possibility of needing further treatment in the future. Active treatment Offer surgery and radiotherapy as alternatives to AS to patients suitable for such treatments and who accept a trade-off between toxicity and prevention of disease progression. Pelvic lymph node dissection (PLND) Do not perform a PLND.

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Strength rating

Strong Weak Strong Strong Strong

Strong Strong Strong Weak

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Radiotherapeutic treatment Offer low-dose rate brachytherapy to patients with low-risk PCa, without a recent transurethral resection of the prostate and a good International Prostatic Symptom Score. Use intensity-modulated radiation therapy plus image-guided radiation therapy with a total dose of 74-80 Gy or moderate hypofractionation (60 Gy/20 fx in 4 weeks or 70 Gy/28 fx in 6 weeks), without androgen deprivation therapy (ADT). Other therapeutic options Do not offer ADT monotherapy to asymptomatic men not able to receive any local treatment. Only offer whole gland treatment (such as cryotherapy, high-intensity focused ultrasound, etc.) or focal treatment within a clinical trial setting or well-designed prospective cohort study.

Strong Strong

Strong Strong

6.2.2 Treatment of intermediate-risk disease When managed with non-curative intent, intermediate-risk PCa is associated with 10-year and 15-year PCSM rates of 13.0% and 19.6%, respectively [796]. 6.2.2.1 Active Surveillance In the ProtecT trial, up to 22% of the randomised patients in the AM arm had ISUP grade > 1 and 10% a PSA > 10 ng/mL [467]. A Canadian consensus group proposes that low volume ISUP grade 2 (< 10% Gleason pattern 4) may also be considered for AS. These recommendations have been endorsed by the American Society of Clinical Oncology (ASCO) [797] and the recent DETECTIVE consensus meeting [252] for those patients with a PSA < 10 ng/mL and low core positivity. However, data is less consistent in other patient groups. It is clear that the presence of any grade 4 pattern is associated with a 3-fold increased risk of metastases compared to ISUP grade 1, while a PSA up to 20 ng/mL might be an acceptable threshold [776, 798, 799]. In addition, it is likely that mpMRI and targeted biopsies will detect small focuses of Gleason 4 cancer that might have been missed with systematic biopsy. Therefore, care must be taken when explaining this treatment strategy especially to patients with the longest life expectancy. 6.2.2.2 Surgery Patients with intermediate-risk PCa should be informed about the results of two RCTs (SPCG-4 and PIVOT) comparing RRP vs. WW in localised PCa. In the SPCG-4 study, death from any cause (RR: 0.71, 95% CI: 0.53–0.95), death from PCa (RR: 0.38, 95% CI: 0.23–0.62) and distant metastases (RR: 0.49, 95% CI: 0.32–0.74) were significantly reduced in intermediate-risk PCa at 18 years. In the PIVOT trial, according to a pre-planned subgroup analysis among men with intermediate-risk tumours, RP significantly reduced all-cause mortality (HR: 0.69, 95% CI: 0.49–0.98), but not death from PCa (0.50, 95% CI: 0.21–1.21) at 10 years. The risk of having positive LNs in intermediate-risk PCa is between 3.7–20.1% [800]. An eLND should be performed in intermediate-risk PCa if the estimated risk for pN+ exceeds 5% [381] or 7% if using the nomogram by Gandaglia et al., which incorporates MRI-guided biopsies [521]. In all other cases eLND can be omitted, which means accepting a low risk of missing positive nodes. 6.2.2.3 Radiation therapy 6.2.2.3.1 Recommended IMRT for intermediate-risk PCa Patients suitable for ADT can be given combined IMRT with short-term ADT (4–6 months) [801-803]. For patients unsuitable for ADT (e.g., due to co-morbidities) or unwilling to accept ADT (e.g. to preserve their sexual health) the recommended treatment is IMRT (76–78 Gy) or a combination of IMRT and brachytherapy (see Section 6.2.3.2.3). 6.2.2.3.2 Brachytherapy monotherapy Low-dose rate brachytherapy can be offered to patients with ISUP grade 2 with < 33% of biopsy cores involved with cancer and without a recent TURP and good IPSS Score. Fractionated HDR brachytherapy as monotherapy can be offered to selected patients with intermediate-risk PCa although they should be informed that results are only available from small series in very experienced centres. Five-year PSA control rates over 90% are reported, with late grade 3+ GU toxicity rates < 5% and no, or very minimal, grade 3+ GI toxicity rates [704, 804]. There are no direct data to inform on the use of ADT in this setting. For the combination of EBRT plus brachytherapy boost please see Section 6.2.3.2.3. 6.2.2.4 Other options for the primary treatment of intermediate-risk PCa (experimental therapies) A prospective study on focal therapy using HIFU in patients with localised intermediate-risk disease was published but the data was derived from an uncontrolled, single-arm case series [773]. There is a paucity of

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high-certainty data for either whole-gland or focal ablative therapy in the setting of intermediate-risk disease. Consequently, neither whole-gland treatment nor focal treatment can be considered as standard therapy for intermediate-risk patients and, if offered, it should only be in the setting of clinical trials [756]. Data regarding the use of ADT monotherapy for intermediate-risk disease have been inferred indirectly from the EORTC 30891 trial, which was a RCT comparing deferred ADT vs. immediate ADT in 985 patients with T0–4 N0–2 M0 disease [800]. The trial showed a small, but statistically significant, difference in OS in favour of immediate ADT monotherapy but there was no significant difference in CSS, predominantly because the risk of cancer-specific mortality was low in patients with PSA < 8 ng/mL. Consequently, the use of ADT monotherapy for this group of patients is not considered as standard, even if they are not eligible for radical treatment. 6.2.2.5

Guidelines for the treatment of intermediate-risk disease

Recommendations Active surveillance (AS) Offer AS to highly selected patients with ISUP grade group 2 disease (i.e. < 10% pattern 4, PSA < 10 ng/mL, < cT2a, low disease extent on imaging and biopsy) accepting the potential increased risk of metastatic progression. Radical prostatectomy (RP) Offer RP to patients with intermediate-risk disease and a life expectancy of > 10 years. Offer nerve-sparing surgery to patients with a low risk of extracapsular disease. Pelvic lymph node dissection (ePLND) Perform an ePLND in intermediate-risk disease (see Section 6.1.2.3.2). Radiotherapeutic treatment Offer low-dose rate brachytherapy to intermediate-risk patients with ISUP grade 2 with < 33% of biopsy cores involved, without a recent transurethral resection of the prostate and with a good International Prostatic Symptom Score. For intensity-modulated radiotherapy (IMRT) plus image-guided radiotherapy (IGRT), use a total dose of 76–78 Gy or moderate hypofractionation (60 Gy/20 fx in 4 weeks or 70 Gy/28 fx in 6 weeks), in combination with short-term androgen deprivation therapy (ADT) (4 to 6 months). In patients not willing to undergo ADT, use a total dose of IMRT plus IGRT (76–78 Gy) or moderate hypofractionation (60 Gy/20 fx in 4 weeks or 70 Gy/28 fx in 6 weeks) or a combination with brachytherapy. Other therapeutic options Only offer whole-gland ablative therapy (such as cryotherapy, high-intensity focused ultrasound, etc.) or focal ablative therapy for intermediate-risk disease within a clinical trial setting or well-designed prospective cohort study. Do not offer ADT monotherapy to intermediate-risk asymptomatic men not able to receive any local treatment.

Strength rating Weak

Strong Strong Strong Strong

Strong

Weak

Strong

Weak

6.2.3 Treatment of high-risk localised disease Patients with high-risk PCa are at an increased risk of PSA failure, need for secondary therapy, metastatic progression and death from PCa. Nevertheless, not all high-risk PCa patients have a uniformly poor prognosis after RP [805]. When managed with non-curative intent, high-risk PCa is associated with 10-year and 15-year PCSM rates of 28.8 and 35.5%, respectively [806]. There is no consensus regarding the optimal treatment of men with high-risk PCa. 6.2.3.1 Radical prostatectomy Provided that the tumour is not fixed to the pelvic wall or there is no invasion of the urethral sphincter, RP is a reasonable option in selected patients with a low tumour volume. Extended PLND should be performed in all high-risk PCa cases [381, 382]. Patients should be aware pre-operatively that surgery may be part of multimodal treatment. 6.2.3.1.1 ISUP grade 4–5 The incidence of organ-confined disease is 26–31% in men with an ISUP grade > 4 on systematic biopsy. A high rate of downgrading exists between the biopsy ISUP grade and the ISUP grade of the resected specimen [806]. Several retrospective case series have demonstrated CSS rates over 60% at 15 years after RP in the

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context of a multi-modal approach (adjuvant or salvage ADT and/or RT) in patients with a biopsy ISUP grade 5 [424, 494, 807, 808]. 6.2.3.1.2 Prostate-specific antigen > 20 ng/mL Reports in patients with a PSA > 20 ng/mL who underwent surgery as initial therapy within a multi-modal approach demonstrated a CSS at 15 years of over 70% [424, 494, 501, 809-811]. 6.2.3.1.3 R  adical prostatectomy in cN0 patients who are found to have pathologically confirmed lymph node invasion (pN1) At 15 years follow-up cN0 patients who undergo RP but who were found to have pN1 were reported to have an overall CSS and OS of 45% and 42%, respectively [812-818]. However, this is a very heterogeneous patient group and further treatment must be individualised based on risk factors (see Sections 6.2.5.2 and 6.2.5.6). 6.2.3.2 External beam radiation therapy 6.2.3.2.1 Recommended external beam radiation therapy treatment policy for high-risk localised PCa For high-risk localised PCa, a combined modality approach should be used consisting of IMRT plus long-term ADT. The duration of ADT has to take into account PS, co-morbidities and the number of poor prognostic factors. It is important to recognise that in several studies EBRT plus short-term ADT did not improve OS in high-risk localised PCa and long-term ADT (at least 2 to 3 years) is currently recommended for these patients [662, 663, 666]. 6.2.3.2.2 Lymph node irradiation in cN0 There is no high level evidence for prophylactic whole-pelvic irradiation since RCTs have failed to show that patients benefit from prophylactic irradiation (46–50 Gy) of the pelvic LNs in high-risk disease [819-821]. In the RTOG 94-13 study there were no PFS differences between patients treated with whole-pelvic or prostate-only RT but interactions between whole-pelvic RT and the duration of ADT were reported following the subgroup analysis [666]. Furthermore, in most trials dealing with high-risk PCa irradiation of a whole pelvis field was considered standard of care. The benefits of pelvic nodal irradiation using IMRT merit further investigation in RCTs as conducted by the RTOG or the UK NCRI group. Performing an ePLND in order to decide whether or not pelvic RT is required (in addition to combined prostate EBRT plus long-term ADT) remains purely experimental in the absence of high level evidence. 6.2.3.2.3 Brachytherapy boost In men with intermediate- or high-risk PCa, brachytherapy boost with supplemental EBRT and hormonal treatment [822] may be considered. External beam RT (total dose of 78 Gy) has been compared with EBRT (total dose 46 Gy) followed by LDR brachytherapy boost (prescribed dose 115 Gy) in intermediate-risk and high-risk patients in a randomised trial with 12 months of ADT in both arms [823]. The LDR boost resulted in 5- and 7-year PSA PFS increase (89% and 86%, respectively, compared to 84% and 75%). This improvement was achieved at a cost of increased late grade 3+ GU toxicity (18% compared to 8%) [824]. Toxicity resulted mainly in the development of urethral strictures and incontinence and great care should be taken during treatment planning. See Section 6.1.3.4.2 for details on a RCT directly comparing EBRT alone and EBRT with HDR brachytherapy boost. The TROG 03.04 RADAR trial randomised men with locally-advanced PCa to 6 or 18 months ADT with an additional upfront radiation dose escalation stratification with dosing options of 66, 70, or 74 Gy EBRT, or 46 Gy EBRT plus HDR brachytherapy boost. After a minimum follow-up of 10 years HDR boost signficantly reduced distant progression, the study primary endpoint (subhazard ratio 0.68 [95% CI: 0.57–0.80]; p < 0.0001), when compared to EBRT alone and independent of duration of ADT [822]. Although radiation dose escalation using brachytherapy boost provides much higher biological doses, the TROG 03.04 RADAR RCT and systematic reviews show ADT use independently predicts better outcomes regardless of radiation dose intensification [822, 825, 826]. Omitting ADT may result in inferior OS and based on current evidence ADT use and duration should be in line with that used when delivering EBRT alone. 6.2.3.3 Options other than surgery and radiotherapy for the primary treatment of localised PCa Currently there is a lack of evidence supporting any other treatment option apart from RP and radical RT in localised high-risk PCa.

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6.2.3.4

Guidelines for radical treatment of high-risk localised disease

Recommendations Radical Prostatectomy (RP) Offer RP to selected patients with high-risk localised PCa as part of potential multi-modal therapy. Extended pelvic lymph node dissection (ePLND) Perform an ePLND in high-risk PCa. Do not perform a frozen section of nodes during RP to decide whether to proceed with, or abandon, the procedure. Radiotherapeutic treatment In patients with high-risk localised disease, use intensity-modulated radiation therapy (IMRT) plus image-guided radiation therapy (IGRT) with 76–78 Gy in combination with long-term androgen deprivation therapy (ADT) (2 to 3 years). In patients with high-risk localised disease, use IMRT and IGRT with brachytherapy boost (either high-dose rate or low-dose rate), in combination with long-term ADT (2 to 3 years). Therapeutic options outside surgery and radiotherapy Do not offer either whole gland or focal therapy to patients with high-risk localised disease. Only offer ADT monotherapy to those patients unwilling or unable to receive any form of local treatment if they have a prostate-specific antigen (PSA)-doubling time < 12 months, and either a PSA > 50 ng/mL or a poorly-differentiated tumour.

Strength rating Strong

Strong Strong

Strong

Weak

Strong Strong

6.2.4 Treatment of locally advanced PCa In the absence of high level evidence a recent systematic review could not define the most optimal treatment option [827]. Randomised controlled trials are only available for EBRT. A local treatment combined with a systemic treatment provides the best outcome, provided the patient is ready and fit enough to receive both. 6.2.4.1 Surgery Surgery for locally advanced disease as part of a multi-modal therapy has been reported [806, 828, 829]. However, the comparative oncological effectiveness of RP as part of a multi-modal treatment strategy vs. upfront EBRT with ADT for locally advanced PCa remains unknown, although a prospective phase III RCT (SPCG-15) comparing RP (with or without adjuvant or salvage EBRT) against primary EBRT and ADT among patients with locally advanced (T3) disease is currently recruiting [830]. Data from retrospective case series demonstrated over 60% CSS at 15 years and over 75% OS at 10 years [804, 806, 828, 829, 831-834]. For cT3b–T4 disease, PCa cohort studies showed 10-year CSS of over 87% and OS of 65% [835-837]. The indication for RP in all previously described stages assumes the absence of clinically detectable nodal involvement (cN0). In case of suspected positive LNs during RP (initially considered cN0) the procedure should not be abandoned since RP may have a survival benefit in these patients. Intra-operative frozen section analysis is not justified in this case [550]. An ePLND is considered standard if a RP is planned. 6.2.4.2 Radiotherapy for locally advanced PCa In locally advanced disease RCTs have clearly established that the additional use of long-term ADT combined with RT produces better OS than ADT or RT alone (see Section 6.1.3.1.4 and Tables 6.1.9 and 6.1.10) [827]. 6.2.4.3 Treatment of cN1 M0 PCa Lymph node metastasised PCa is where options for local therapy and systemic therapies overlap. Approximately 5% to 10% of newly diagnosed PCa patients have synchronous suspected pelvic nodal metastases on conventional imaging (CT/bone scan) without bone or visceral mestatases (cN1 M0 stage). Meta-analyses have shown that PSMA-PET/CT prior to primary treatment in advanced PCa detected disease outside the prostate in 32% of cases despite prior negative conventional imaging using bone scan and pelvic CT/MRI [397]. A RCT assessing PSMA-PET/CT as staging tool in high-risk PCa confirmed these findings and showed a 32% increase in accuracy compared with conventional imaging for the detection of pelvic nodal metastases [417]. Notably, more sensitive imaging also causes a stage shift with more cases classified as cN1, but with, on average, lower nodal disease burden. The management of cN1 PCa is mainly based on long-term ADT. The benefit of adding local treatment has been assessed in various retrospective studies, summarised in one systematic review [839] including 5 studies only dealing with cN1M0 patients [840-844]. The findings suggested an advantage in both OS and CSS after local treatment (RT or RP) combined with ADT as compared to ADT alone. The main limitations of this analysis

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were the lack of randomisation, of comparisons between RP and RT, as well as the value of the extent of PLND and of RT fields. Only limited evidence exists supporting RP for cN+ patients. Moschini et al., compared the outcomes of 50 patients with cN+ with those of 252 patients with pN1, but cN0 at preoperative staging. cN+ was not a significant predictor of CSS [838]. Based on the consistent benefit seen in retrospective studies including cN1 patients local therapy is recommended in patients with cN1 disease at diagnosis in addition to long-term ADT (see Table 6.2.4.1). The intensification of systemic treatment (abiraterone acetate, docetaxel, zoledronic acid) has been assessed in unplanned sub-group analyses from the STAMPEDE multi-arm RCT by stratifying for cN+ and M+ status [40, 843]. The analyses were balanced for nodal involvement and for planned RT use in STAMPEDE at randomisation and at analysis. Abiraterone acetate was associated with a non-significant OS improvement (HR: 0.75, 95% CI: 0.48–1.18) in non-metastatic patients (N0/N+M0), but OS data were still immature with a low number of events. Furthermore, this was an underpowered subgroup analysis and hypothesis generating at best. Moreover, subgroup analyses were performed according to the metastatic/non-metastatic status and to the nodal status (any M) without specific data for the N+M0 population (n = 369; 20% of the overall cohort). The same would apply for the docetaxel arm in the STAMPEDE trial for which no specific subgroup analysis of newly diagnosed N+M0 PCa (n = 171, 14% of the overall cohort) was performed. However, the addition of docetaxel, zoledronic acid, or their combination, did not provide any OS benefit when stratifying by M0 and N+ status. Table 6.2.4.1: Selected studies assessing local treatment in (any cT) cN1 M0 prostate cancer patients Study

n

Design

Bryant, et al. 2018 [845]

n = 648

Retrospective (National Veterans Affairs) 61 mo.

Sarkar, et al. 2019 [846]

n = 741

2000-2015 Retrospective (National Veterans Affairs) 51 mo.

Lin, et al. 2015 [841]

Tward, et al. 2013 [840]

Retrospective n = 983 (NCDB) before propensity score matching n = 1,100 Retrospective (SEER)

Study period/ Treatment follow-up arms 2000-2015 ADT ± EBRT

2004-2006

64 mo.

Rusthoven, n = 796 et al. 2014 [844]

Retrospective (SEER)

1995-2005 61 mo.

Seisen, et al. 2018 [842]

n = 1,987

Retrospective (NCDB)

2003-2011 50 mo.

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Significant benefit for combined treatment only if PSA levels less than the median (26 ng/mL) All-cause mortality HR: 0.50 CSS, HR: 0.38 ADT ± local Significant benefit for RP treatment All cause mortality HR 0.36 (surgery or RT) CSS, HR: 0.32

ADT ± EBRT

48 mo.

1988-2006

Effect on survival

EBRT (n = 397) vs. no EBRT (n=703) No information on ADT) EBRT vs. no EBRT (no information on ADT) ADT ± local treatment (surgery or RT)

No statistical difference for RP vs. RT (p > 0.1) All-cause mortality HR: 047 CSS, HR: 0.88 Significant benefit for combined treatment 5-yr OS: 73% vs. 52% HR: 0.5 Significant benefit for EBRT 5-yr CSS (not OS?) 78% vs. 71% HR: 0.66 5-yr. OS: 68% vs. 56%, HR: 0.70 Significant benefit for EBRT 10-yr OS: 45% vs. 29% HR: 0.58 Significant benefit for combined treatment 5-yr OS: 78.8% vs. 49.2% HR: 0.31 No difference between RP and RT

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James, et al. 2016 [843]

n = 177

Unplanned sub- 2005-2014 group analysis RCT 17 mo.

ADT ± EBRT

Significant benefit for combined treatment 5-yr OS: 93% vs. 71% 2-yr FFS: 81% vs 53% FFS, HR: 0.48

ADT = androgen deprivation therapy; EBRT = external beam radiotherapy in standard fractionation; FFS = failure-free survival; HR = hazard ratio; mo = months; n = number of patients; OS = overall survival; RT = radiotherapy; wk = week; yr = year. 6.2.4.3.1 Guidelines for the management of cN1 M0 prostate cancer Recommendations Offer patients with cN1 disease a local treatment (either radical prostatectomy or intensity modulated radiotherapy plus image-guided radiotherapy) plus long-term ADT.

Strength rating Weak

6.2.4.4 Options other than surgery and radiotherapy for primary treatment 6.2.4.4.1 Investigational therapies Currently cryotherapy, HIFU or focal therapies have no place in the management of locally-advanced PCa. 6.2.4.4.2 Androgen deprivation therapy monotherapy The deferred use of ADT as single treatment modality has been answered by the EORTC 30891 trial [800]. Nine hundred and eighty-five patients with T0-4 N0-2 M0 PCa received ADT alone, either immediately or after symptomatic progression or occurrence of serious complications. After a median follow-up of 12.8 years, the OS favoured immediate treatment (HR: 1.21, 95% CI: 1.05–1.39). Surprisingly, no different disease-free or symptom-free survival was observed, raising the question of survival benefit. In locally-advanced T3-T4 M0 disease unsuitable for surgery or RT, immediate ADT may only benefit patients with a PSA > 50 ng/mL and a PSA-DT < 12 months or those that are symptomatic [800, 847]. The median time to start deferred treatment was 7 years. In the deferred treatment arm 25.6% died without needing treatment. 6.2.4.5

Guidelines for radical treatment of locally-advanced disease

Recommendations Radical Prostatectomy (RP) Offer RP to selected patients with locally-advanced PCa as part of multi-modal therapy. Extended pelvic lymph node dissection (ePLND) Perform an ePLND prior to RP in locally-advanced PCa. Radiotherapeutic treatments In patients with locally-advanced disease, offer intensity-modulated radiation therapy (IMRT) plus image-guide radiation therapy in combination with long-term androgen deprivation therapy (ADT). Offer long-term ADT for at least 2 years. Therapeutic options outside surgery and radiotherapy Do not offer whole gland treatment or focal treatment to patients with locally-advanced PCa. Only offer ADT monotherapy to those patients unwilling or unable to receive any form of local treatment if they have a prostate-specific antigen (PSA)-doubling time < 12 months, and either a PSA > 50 ng/mL, a poorly-differentiated tumour or troublesome local disease-related symptoms. Offer patients with cN1 disease a local treatment (either RP or IMRT plus IGRT) plus long-term ADT.

Strength rating Strong Strong Strong

Weak Strong Strong

Strong

6.2.5 Adjuvant treatment after radical prostatectomy 6.2.5.1 Introduction Adjuvant treatment is by definition additional to the primary or initial therapy with the aim of decreasing the risk of relapse. A post-operative detectable PSA is an indication of persistent prostate cells (see Section 6.2.6). All information listed below refers to patients with a post-operative undetectable PSA.

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6.2.5.2 Risk factors for relapse Patients with ISUP grade > 2 in combination with extraprostatic extension (pT3a) and particularly those with SV invasion (pT3b) and/or positive surgical margins are at high risk of progression, which can be as high as 50% after 5 years [850]. Irrespective of the pT stage, the number of removed nodes [851-858], tumour volume within the LNs and capsular perforation of the nodal metastases are predictors of early recurrence after RP for pN1 disease [859]. A LN density (defined as ‘the percentage of positive LNs in relation to the total number of analysed/removed LNs’) of over 20% was found to be associated with poor prognosis [860]. The number of involved nodes seems to be a major factor for predicting relapse [853, 854, 861]; the threshold considered is less than 3 positive nodes from an ePLND [512, 853, 861]. However, prospective data are needed before defining a definitive threshold value. 6.2.5.2.1 Biomarker-based risk stratification after radical prostatectomy The Decipher® gene signature consists of a 22-gene panel representing multiple biological pathways and was developed to predict systemic progression after definitive treatment. A meta-analysis of five studies analysed the performance of the Decipher® Genomic Classifier (GC) test on men post-RP. The authors showed in multivariable analysis that Decipher® GC remained a statistically significant predictor of metastasis (HR: 1.30, 95% CI: 1.14–1.47, p < 0.001) per 0.1 unit increase in score and concluded that it can independently improve prognostication of patients post-RP within nearly all clinicopathologic, demographic, and treatment subgroups [862]. Further studies are needed to establish how to best incorporate Decipher® GC in clinical decisionmaking. 6.2.5.3 Immediate (adjuvant) post-operative external irradiation after RP (cN0 or pN0) Four prospective RCTs have assessed the role of immediate post-operative RT (adjuvant RT [ART]), demonstrating an advantage (endpoint, development of BCR) in high-risk patients (e.g., pT2/pT3 with positive surgical margins and GS 8–10) post-RP (Table 6.2.5.1). In the ARO 96-02 trial, 80% of the pT3/R1/GS 8–10 patients randomised to observation developed BCR within 10 years. It must be emphasised that PSA was undetectable at inclusion only in the ARO 96-02 trial which presents a major limitation interpreting these findings as patients with a detectable PSA would now be considered for salvage therapy rather than ART [863]. Table 6.2.5.1: O  verview of all four randomised trials for adjuvant surgical bed radiation therapy after RP* (without ADT) Reference

n

SWOG 8794 431 2009 [863]

EORTC 22911 2012 [864]

ARO 96-02 2014 [865]

Inclusion criteria pT3 cN0 ± involved SM

1,005 pT3 ± involved SM pN0 pT2 involved SM pN0 388 pT3 (± involved SM) pN0 PSA post-RP undetectable

Overall survival

Median Randomisation Definition of BCR PSA (ng/ FU (mo) mL) 60-64 Gy vs. > 0.4 152 observation

Biochemical Progressionfree survival 10 yr.: 53% vs. 30% (p < 0.05)

60 Gy vs. observation

> 0.2

127

10 yr.: 60.6% vs. 41% (p < 0.001)

60 Gy vs. observation

> 0.05 + confirmation

112

10 yr.: 56% vs. 10 yr.: 82% vs. 35% 86% n.s. (p = 0.0001)

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10 yr.: 74% vs. 66% Median time: 15.2 vs. 13.3 yr., p = 0.023 81% vs. 77% n.s.

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FinnProstate 250 Group 2019 [866]

pT2,R1/ pT3a

66.6 Gy vs. observation (+SRT)

112 vs. 10 yr.: 82% vs. 10 yr.: > 0.4 (in 2 92% vs. 61% 103 successive 87% n.s. measurements) (patients p  0.4 ng/mL after RT. The primary endpoint for RAVES and GETUG-AFU 17 was biochemical PFS and for RADICALS-RT metastasis-free survival. So far only PFS data has been reported, and not metastasis-free survival or OS data. With a median follow-up between 4.9 years and 6.25 years there was no statistical significant difference for biochemical PFS (BPFS) for both treatments in all three trials (see Table 6.2.5.2) indicating that in the majority of patients adjuvant irradiation should be avoided. Additionally, there was a significant lower rate of grade > 2 GU late side effects and grade 3–4 urethral strictures in favour of early SRT; which may also be caused by the low number of patients with PSA-progression and subsequent need for early SRT at the time of analysis (40% of patients). It is important to note that the indication for ART changed over the last ten years with the introduction of ultrasensitive PSA-tests, favouring early SRT. Therefore many patients, randomised in these three trials (accruing 2006–2008) are not likely to benefit from ART as there is a low risk of biochemical progression (~20–30%) in, for example, pT3R0- or pT2R1-tumours. The median pre-SRT-PSA in all 3 trials was 0.24 ng/mL which is much lower than the conventional cut-off level of PSA < 0.5 ng/mL used to base ´early´ SRT on. Therefore, patients with ‘low-risk factors’ of biochemical progression after RP should be closely followed up with ultra-senstive assays and SRT should start as soon as PSA starts to rise, which has to be confirmed by a second PSA measurement. The proportion of ´very high risk´ patients (with at least two out of three features: pT3/R1/GS 8-10) in all three trials was low (between 10–20%) and therefore even the meta-analysis may be underpowered to show an outcome in favour of SRT [873]. In addition, the side-effect profile may have been impacted with a larger proportion of ART patients receiving treatment with older 3D-treatment planning techniques as compared to SRT patients (GETUG-AFU 17: ART, 69% 3D vs. 46% SRT) and patients treated more recently were more likely to undergo IMRT techniques with a proven lower rate of late side effects [610]. For these reasons 10-year results and results of metastasis-free survival endpoints should be awaited before drawing final conclusions. Due to the small number of patients with a combination of high-risk features included in these three trials (between 10–20%) ART remains a recommended treatment option in highly selected patients with at least two out of three high-risk features (‘very high-risk patients’) such as pT3/R1/ ISUP > 3 [854, 874].

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Table 6.2.5.2 O  verview of all four randomised trials and one meta-analysis for patients treated with adjuvant versus early salvage RT after radical prostatectomy Reference

n

Inclusion criteria

Randomisation Definition of BCR PSA (ng/mL) > 0.4 post pT3a/pT3b 64 Gy ART 333 RAVES TROG 08.03/ target any T - SM+ PSA: (< 0.1) vs. RT 64 Gy early SRT PSA postwas ANZUP at PSA > 0.2 RP: < 0.1 470 2020 [871] med. pre-SRT: early n.r. closed 52.5 Gy (20 Fx) > 0.4 or 2 at RADICALS- 1,396 pT3a/ or 66 Gy (33 Fx) any time pT3b/pT4 RT ART PSA > 10 2020 [870] early SRT pre-RP any T, SM+ identical at PSA > 0.1 Gleason med.pre-SRT: 7-10 0.2 PSA post RP: < 0.2 GETUG-AFU 424 target 17 was 2020 [872] 718 early closed

pT3a/pT3b/ pT4a and SM+ PSA post-RP: < 0.1

2,153 ARTISTICMeta-analysis 2020 [873]

see above

66 Gy (ART) vs. > 0.4 66 Gy early SRT at PSA 0.1 both groups: 6 mo. LHRH-A med. pre-SRT 0.24 see above see above

Median BPFS FU (yr)

OS or Side effects MFS

6.1

n.r. 5 yr.: 86% vs. 87% (p > 0.05)

LT grade > GU: 70% vs. 54% (p = 0.002)

4.9

n.r. 5 yr.: 85% vs. 88% (p = 0.56)

6.25

n.r. 5 yr: 92% vs. 90% (p = 0.42)

4.5

5 yr.: 89% vs. 88% p = 0.7

SR urinary incontinence 1yr: 4.8 vs. 4 (p = 0.023) urethral stricture grade 3/4 2 yr: 6% vs. 4% (p = 0.02) LT grade > 2 GU 27% vs. 7% (p < 0.001) ED: 28% vs. 8% (p < 0.001) n.r.

n.r.

ART = adjuvant radiotherapy; BCR = biochemical recurrence; BPFS = biochemical progression-free survival; ED = erectile dysfunction; FU = follow-up; Fx = fraction; GU = genitourinary; LT = late toxicity; mo = months; med = median; MFS = metastasis-free survival; n.r. = not reported; OS = overall survival; RP = radical prostatectomy; RT = radiotherapy; SR = self reported; SRT = salvage radiotherapy; + = positive; yr = year. 6.2.5.5 Adjuvant androgen ablation in men with N0 disease Adjuvant androgen ablation with bicalutamide 150 mg daily did not improve PFS in localised disease while it did for locally-advanced disease after RT. However this never translated to an OS benefit [875]. A systematic review showed a possible benefit for PFS but not OS for adjuvant androgen ablation [489]. The TAX3501 trial comparing the role of leuprolide (18 months) with and without docetaxel (6 cycles) ended prematurely due to poor accrual. A recent phase III RCT comparing adjuvant docetaxel against surveillance after RP for locally-advanced PCa showed that adjuvant docetaxel did not confer any oncological benefit [876]. Consequently, adjuvant chemotherapy after RP should only be considered in a clinical trial [877]. 6.2.5.6 Adjuvant treatment in pN1 disease 6.2.5.6.1 Adjuvant androgen ablation alone The combination of RP and early adjuvant HT in pN+ PCa has been shown to achieve a 10-year CSS rate of 80% and has been shown to significantly improve CSS and OS in prospective RCTs [848, 849]. However, these trials included mostly patients with high-volume nodal disease and multiple adverse tumour characteristics and these findings may not apply to men with less extensive nodal metastases. 6.2.5.6.2 Adjuvant radiotherapy combined with ADT in pN1 disease In a retrospective multi-centre cohort study, maximal local control with RT to the prostatic fossa appeared to be beneficial in PCa patients with pN1 after RP, treated ‘adjuvantly‘ with continuous ADT (within 6 months after surgery irrespective of PSA). The beneficial impact of adjuvant RT on survival in patients with pN1 PCa was

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highly influenced by tumour characteristics. Men with low-volume nodal disease (< 3 LNs), ISUP grade 2–5 and pT3–4 or R1, as well as men with 3 to 4 positive nodes were more likely to benefit from RT after surgery, while the other subgroups did not [878]. These results were confirmed by a US National Cancer Database analysis based on 5,498 patients [879]. Another US National Cancer Database study including 8,074 pN1 patients reports improved OS after ADT + EBRT (including pelvic LNs) vs. observation and vs. ADT alone in all men with single or multiple adverse pathological features. Men without any adverse pathological features did not benefit from immediate adjuvant therapy [880]. In a series of 2,596 pN1 patients receiving ADT (n = 1,663) or ADT plus RT (n = 906), combined treatment was associated with improved OS, with a HR of 1.5 for ADT alone [881]. In a SEER retrospective population-based analysis, adding RT to RP showed a non-significant trend for improved OS but not PCa-specific survival, but data on the extent of additional RT is lacking in this study [844]. Radiotherapy should be given to the pelvic lymphatics and the prostatic fossa [878, 882-884]. For pN1 patients no data are available regarding adjuvant EBRT without ADT. 6.2.5.6.3 Observation of pN1 patients after radical prostatectomy and extended lymph node dissection Several retrospective studies and a systematic review addressed the management of patients with pN1 PCa at RP [861, 878, 884-886]. A subset of patients with limited nodal disease (1–2 positive LNs) showed favourable oncological outcomes and did not require additional treatment. An analysis of 209 pN1 patients with one or two positive LNs at RP showed that 37% remained metastasis-free without need of salvage treatment at a median follow-up of 60.2 months [885]. Touijer et al. reported their results of 369 LN-positive patients (40 with and 329 without adjuvant treatment) and showed that higher pathologic grade group and three or more positive LNs were significantly associated with an increased risk of BCR on multivariable analysis [861]. Biochemical-free survival rates in pN1 patients without adjuvant treatment ranged from 43% at 4 years to 28% at 10 years [886]. Reported CSS rates were 78% at 5 years and 72% at 10 years. The majority of these patients were managed with initial observation after surgery, had favourable disease characteristics, and 63% had only one positive node [886]. 6.2.5.7

Guidelines for adjuvant treatment in pN0 and pN1 disease after radical prostatectomy

Recommendations Do not prescribe adjuvant androgen deprivation therapy (ADT) in pN0 patients. Only offer adjuvant intensity-modulated radiation therapy (IMRT) plus image-guided radiation therapy (IGRT) to high-risk patients (pN0) with at least two out of three high-risk features (ISUP grade group 4–5, pT3 ± positive margins). Discuss three management options with patients with pN1 disease after an extended lymph node dissection, based on nodal involvement characteristics: 1. Offer adjuvant ADT; 2. Offer adjuvant ADT with additional IMRT plus IGRT; 3. O  ffer observation (expectant management) to a patient after eLND and < 2 nodes and a PSA < 0.1 ng/mL. 6.2.5.8

Strength rating Strong Strong

Weak

Guidelines for non-curative or palliative treatments in prostate cancer

Recommendations Strength rating Watchful waiting (WW) for localised prostate cancer Offer WW to asymptomatic patients not eligible for local curative treatment and those with a Strong short life expectancy. Watchful waiting for locally-advanced prostate cancer Weak Offer a deferred treatment policy using androgen deprivation monotherapy to M0 asymptomatic patients with a prostate-specific antigen (PSA) doubling time > 12 months, a PSA < 50 ng/mL and well-differentiated tumour, who are unwilling or unable to receive any form of local treatment.

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6.2.6 Persistent PSA after radical prostatectomy Between 5 and 20% of men continue to have detectable or persistent PSA after RP (when defined in the majority of studies as detectable post-RP PSA of > 0.1 ng/mL within 4 to 8 weeks of surgery) [887, 888]. It may result from persistent local disease, pre-existing metastases or residual benign prostate tissue. 6.2.6.1 Natural history of persistently elevated PSA after RP Several studies have shown that persistent PSA after RP is associated with more advanced disease (such as positive surgical margins (PSM), pathologic stage > T3a, positive nodal status and/or pathologic ISUP grade > 3) and poor prognosis (See table 6.2.6.1). Initially defined as > 0.1 ng/mL, improvements in the sensitivity of PSA assays now allow for the detection of PSA at much lower levels. Moreira et al., demonstrated that failure to achieve a PSA of less than 0.03 ng/mL within 6 months of surgery was associated with an increased risk of BCR and overall mortality [889, 890]. However, since the majority of the published literature is based on the > 0.1 ng/mL PSA cut-off there is significantly more longterm data for this definition. Predictors of PSA persistence were higher BMI, higher pre-operative PSA and ISUP grade > 3 [890]. In patients with PSA persistence, one and 5-year BCR-free survival were 68% and 36%, compared to 95% and 72%, respectively, in men without PSA persistence [889]. Ten-year OS in patients with and without PSA persistence was 63% and 80%, respectively. In line with these data, Ploussard et al. reported that approximately 74% of patients with persistent PSA develop BCR [887]. Spratt et al., confirmed that a persistently detectable PSA after RP represents one of the worst prognostic factors associated with oncological outcome [891]. Of 150 patients with a persistent PSA, 95% received RT before detectable metastasis. In a multivariable analysis the presence of a persistently detectable PSA post-RP was associated with a 4-fold increase in the risk of developing metastasis. This was confirmed by recent data from Preisser et al. who showed that persistent PSA is prognostic of an increased risk of metastasis and death [892]. At 15 years after RP, metastasis-free survival rates, OS and CSS rates were 53.0 vs. 93.2% (p < 0.001), 64.7 vs. 81.2% (p < 0.001) and 75.5 vs. 96.2% (p < 0.001) for persistent vs. undetectable PSA, respectively. The median follow-up was 61.8 months for patients with undetectable PSA vs. 46.4 months for patients with persistent PSA. In multivariable Cox regression models, persistent PSA represented an independent predictor for metastasis (HR: 3.59, p < 0.001), death (HR: 1.86, p < 0.001) and cancer-specific death (HR: 3.15, p < 0.001). However, not all patients with persistent PSA after RP experience disease recurrence. Xiang et al., showed a 50% 5-year BCR-free survival in men who had a persistent PSA level > 0.1 but < 0.2 ng/mL at 6-8 weeks after RP [893]. Rogers et al., assessed the clinical outcome of 160 men with a persistently detectable PSA level after RP [894]. No patient received adjuvant therapy before documented metastasis. In their study, 38% of patients had no evidence of metastases for > 7 years while 32% of the patients were reported to develop metastases within 3 years. Noteworthy is that a significant proportion of patients had low-risk disease. In multivariable analysis the PSA slope after RP (as calculated using PSA levels 3 to 12 months after surgery) and pathological ISUP grade were significantly associated with the development of distant metastases. Table 6.2.6.1: Studies on the natural history of patients with persistent PSA after RP Authors

Study n population Ploussard 496 men pN0 with et al., persistent J Urol PSA 14 2013 centres [887] 1998 - 2011

Definition PSA Treatment Outcome persistence PSA > 0.1 ng/mL 74.4% with at 6 wk. BCR 5% with metastasis

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Other details/comments

85

Moreira et al., BJUI 2010 [890]

901 men Shared Equal Access Regional Cancer Hospital (SEARCH) database. 2001-2008

230

Moreira et al., J Urol 2009 [889]

1,156 men Shared Equal Access Regional Cancer Hospital (SEARCH) database. After 1997

291 (10 pN1)

Rogers et al., Cancer 2004 [894]

224 men Singlecentre (Johns Hopkins) 1989 - 2002

160 men (58 pN1)

Relative to men with undetectable PSA levels, those with a PSA nadir of 0.03 (HR: 3.88, p < 0.001), 0.04 (HR: 4.87, p < 0.001), 0.05-0.09 (HR: 12.69, p < 0.001), 0.1-0.19 (HR: 13.17, p < 0.001), and 0.2 ng/mL (HR: 13.23, p < 0.001) were at increased risk of BCR while men with a nadir of 0.01 (HR: 1.36, p = 0.400) and 0.02 (HR: 1.64, p = 0.180) were not. Median FU 48 mo. In patients PSA > 0.03 ng/mL No RT info Increased with persistent PSA 1 and within 6 mo. BCR and 5-yr. BFS was 68% and 36%, overall significantly lower than 95% mortality and 72%, respectively, in men without persistent PSA. 10-year OS in patients with vs. without persistent PSA was 63% vs. 80%. In men with persistent PSA independent predictors of BCR were higher PSA nadir (HR: 2.19, p < 0.001), positive surgical margins (HR: 1.75, p = 0.022) and high pathological ISUP grade (4-5 vs. 1, HR: 2.40, p = 0.026). Independent predictors of OM were a higher PSA nadir (HR: 1.46, p 0.013) and seminal vesicle invasion (HR: 3.15, p = 0.047) > Metastasis- Mean FU 5.3 yr. 75 men PSA 0.1 ng/mL No at 3 mo. treatment free survival (47%) developed distant at 3, 5 and metastases after RP (median before 10 yr. was onset of time to metastases 5.0 yr.; metastasis 68%, 49%, range, 0.5-13 yr.). and 22%, respectively. The slope of PSA changes approximately 3-12 mo. after RP at a cut-off value > 0.05 ng/mL was found to be predictive of distant metastasis-free survival (HR: 2.9, p < 0.01). No RT info Increased (8 pN1) PSA risk for BCR persistence after surgery definition of a PSA nadir > 0.03 ng/mL

BCR = biochemical recurrence; FU = follow-up; HR = hazard ratio; mo = months; n = number of patients; OM = overall mortality; PSA = prostate-specific antigen; RT = radiotherapy. 6.2.6.2 Imaging in patients with persistently elevated PSA after RP Standard imaging with bone scan and MRI has a low pick-up rate in men with a PSA below 2 ng/mL. However, PSMA PET/CT has been shown to identify residual cancer with positivity rates of 33%, 46%, 57%, 82%, and 97%, in men with post-RP PSA ranges of 0–0.19, 0.2–0.49, 0.5–0.99, 1–1.99, and > 2 ng/mL, respectively [397, 895-899] which can guide SRT planning [900]. Based on these post-RP PSA ranges, Schmidt-Hegemann et al. studied 129 patients who had either persistent PSA (52%) or BCR (48%) after RP, showing that men with a persistent PSA had significantly more pelvic nodal involvement on PSMA PET/CT than those developing a detectable PSA [901]. In a multi-centre retrospective study including 191 patients, 68Ga-PSM localised biochemical persistence after RP in more than two-thirds of patients with high-risk PCa features. The obturator

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and presacral/mesorectal nodes were identified as high risk for residual disease [902]. Another retrospective study included 150 patients with persistent PSA after RARP who were re-staged with both 68Ga-PSMA and 18F-DCFPyL PSMA. The authors found that in the presence of persistent PSA the majority of patients already had metastatic pelvic LNs or distant metastases which would support a role of PSMA PET/CT imaging in guiding (salvage) treatment strategies [903]. At present there is uncertainty regarding the best treatment if PSMA PET/CT shows metastatic disease. 6.2.6.3 Impact of post-operative RT and/or ADT in patients with persistent PSA The benefit of SRT in patients with persistent PSA remains unclear due to a lack of RCTs, however, it would appear that men with a persistent PSA do less well than men with BCR undergoing RT. Wiegel et al., [888] showed that following salvage RT to the prostate bed, patients with a detectable PSA after RP had significantly worse oncological outcomes when compared with those who achieved an undetectable PSA. Ten-year metastasis-free survival was 67% vs. 83% and OS was 68% vs. 84%, respectively. Recent data from Preisser et al., [892] also compared oncological outcomes of patients with persistent PSA who received SRT vs. those who did not. In the subgroup of patients with persistent PSA, after 1:1 propensity score matching between patients with SRT vs. no RT, OS rates at 10 years after RP were 86.6 vs. 72.6% in the entire cohort (p < 0.01), 86.3 vs. 60.0% in patients with positive surgical margin (p = 0.02), 77.8 vs. 49.0% in pT3b disease (p < 0.001), 79.3 vs. 55.8% in ISUP grade 1 disease (p < 0.01) and 87.4 vs. 50.5% in pN1 disease (p < 0.01), respectively. Moreover, CSS rates at 10 years after RP were 93.7 vs. 81.6% in the entire cohort (p < 0.01), 90.8 vs. 69.7% in patients with positive surgical margin (p = 0.04), 82.7 vs. 55.3% in pT3b disease (p < 0.01), 85.4 vs. 69.7% in ISUP grade 1 disease (p < 0.01) and 96.2 vs. 55.8% in pN1 disease (p < 0.01), for SRT vs. no RT, respectively. In multivariable models, after 1:1 propensity score matching, SRT was associated with lower risk for death (HR: 0.42, p = 0.02) and lower cancer-specific death (HR: 0.29, p = 0.03). These survival outcomes in patients with persistent PSA who underwent SRT suggest they benefit but outcomes are worse than for men experiencing BCR. It is clear from a number of studies that poor outcomes are driven by the level of pre-RT PSA, the presence of ISUP grade > 4 in the RP histology and pT3b disease [888, 904-908]. Fossati et al., suggested that only men with a persistent PSA after RP and ISUP grade < 3 benefit significantly [909], although this is not supported by Preisser et al. [892]. The current data does not allow making any clear treatment decisions. Addition of ADT may improve PFS [904]. Choo et al. studied the addition of 2-year ADT to immediate RT to the prostate bed in patients with pathologic T3 disease (pT3) and/or positive surgical margins after RP [904]. Twenty-nine of the 78 included patients had persistently detectable post-operative PSA. The relapse-free rate was 85% at 5 years and 68% at 7 years, which was superior to the 5-year progression-free estimates of 74% and 61% in the post-operative RT arms of the EORTC and the SWOG studies, respectively, which included patients with undetectable PSA after RP [863, 864]. Patients with persistently detectable post-operative PSA comprised approximately 50% and 12%, respectively, of the study cohorts in the EORTC and the SWOG studies. In the ARO 96-02, a prospective RCT, 74 patients with PSA persistence (20%) received immediate SRT only (66 Gy per protocol [arm C]). The 10-year clinical relapse-free survival was 63% [888]. The GETUG-22 trial comparing RT with RT plus short-term ADT for post-RP PSA persistence (0.2–2.0 ng/mL) reported good tolerability of the combined treatment. The oncological endpoints are yet to be published [910]. Ploussard and colleagues recently performed a systematic review of oncologic outcomes and effectiveness of salvage therapies in men with persistent PSA after RP. Their findings confirmed a strong correlation of PSA persistence with poor oncologic outcomes [911]. The authors also report that SRT was associated with improved survival outcomes, although the available evidence is of low quality [911]. 6.2.6.4 Conclusion The available data suggest that patients with PSA persistence after RP may benefit from early aggressive multimodality treatment, however, the lack of prospective RCTs makes firm recommendations difficult.

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6.2.6.5

Recommendations for the management of persistent PSA after radical prostatectomy

Recommendations Offer a prostate-specific membrane antigen positron emission tomography (PSMA PET) scan to men with a persistent prostate-specific antigen > 0.2 ng/mL if the results will influence subsequent treatment decisions. Treat men with no evidence of metastatic disease with salvage radiotherapy and additional hormonal therapy.

6.3

Strength rating Weak

Weak

Management of PSA-only recurrence after treatment with curative intent

Follow-up will be addressed in Chapter 7 and is not discussed here. 6.3.1 Background Between 27% and 53% of all patients undergoing RP or RT develop a rising PSA (PSA recurrence). Whilst a rising PSA level universally precedes metastatic progression, physicians must inform the patient that the natural history of PSA-only recurrence may be prolonged and that a measurable PSA may not necessarily lead to clinically apparent metastatic disease. Physicians treating patients with PSA-only recurrence face a difficult set of decisions in attempting to delay the onset of metastatic disease and death while avoiding overtreating patients whose disease may never affect their OS or QoL. It should be emphasised that the treatment recommendations for these patients should be given after discussion in a multidisciplinary team. 6.3.2 Definitions of clinically relevant PSA relapse The PSA level that defines treatment failure depends on the primary treatment. Patients with rising PSA after RP or primary RT have different risks of subsequent symptomatic metastatic disease based on various parameters, including the PSA level. Therefore, physicians should carefully interpret BCR endpoints when comparing treatments. After RP, the threshold that best predicts further metastases is a PSA > 0.4 ng/mL and rising [912914]. However, with access to ultra-sensitive PSA testing, a rising PSA much below this level will be a cause for concern for patients. After primary RT, with or without short-term hormonal manipulation, the RTOG-ASTRO Phoenix Consensus Conference definition of PSA failure (with an accuracy of > 80% for clinical failure) is ‘any PSA increase > 2 ng/mL higher than the PSA nadir value, regardless of the serum concentration of the nadir’ [915]. After HIFU or cryotherapy no endpoints have been validated against clinical progression or survival; therefore, it is not possible to give a firm recommendation of an acceptable PSA threshold after these alternative local treatments [916]. 6.3.3 Natural history of biochemical recurrence Once a PSA relapse has been diagnosed, it is important to determine whether the recurrence has developed at local or distant sites. A recent systematic review and meta-analysis investigated the impact of BCR on hard endpoints and concluded that patients experiencing BCR are at an increased risk of developing distant metastases, PCa-specific and overall mortality [916]. However, the effect size of BCR as a risk factor for mortality is highly variable. After primary RP its impact ranges from HR 1.03 (95% CI: 1.004–1.06) to HR 2.32 (95% CI: 1.45–3.71) [917, 918]. After primary RT, OS rates are approximately 20% lower at 8 to 10 years follow-up even in men with minimal co-morbidity [919, 920]. Still, the variability in reported effect sizes of BCR remains high and suggests that only certain patient subgroups with BCR might be at an increased risk of mortality. The risk of subsequent metastases, PCa-specific- and overall mortality may be predicted by the initial clinical and pathologic factors (e.g., T-category, PSA, ISUP grade) and PSA kinetics (PSA-DT and interval to PSA failure), which was further investigated by this systematic review [916]. For patients with BCR after RP, the following outcomes were found to be associated with significant prognostic factors: • distant metastatic recurrence: positive surgical margins, high RP specimen pathological ISUP grade, high pT category, short PSA-DT, high pre-SRT PSA; • prostate-cancer-specific mortality: high RP specimen pathological ISUP grade, short interval to biochemical failure as defined by investigators, short PSA-DT; • overall mortality: high RP specimen pathological ISUP grade, short interval to biochemical failure, high PSA-DT.

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For patients with BCR after RT, the corresponding outcomes are: • distant metastatic recurrence: high biopsy ISUP grade, high cT category, short interval to biochemical failure; • prostate-cancer-specific mortality: short interval to biochemical failure; • overall mortality: high age, high biopsy ISUP grade, short interval to biochemical failure, high initial (pre-treatment) PSA. Based on this meta-analysis, proposal is to stratify patients into ‘EAU Low-Risk BCR’ (PSA-DT > 1 year AND pathological ISUP grade < 4 for RP; interval to biochemical failure > 18 months AND biopsy ISUP grade < 4 for RT) or ‘EAU High-Risk BCR’ (PSA-DT < 1 year OR pathological ISUP grade 4–5 for RP, interval to biochemical failure < 18 months OR biopsy ISUP grade 4–5 for RT), since not all patients with BCR will have similar outcomes. The stratification into ‘EAU Low-Risk’ or ‘EAU High-Risk’ BCR has recently been validated in a European cohort [921]. 6.3.4 The role of imaging in PSA-only recurrence Imaging is only of value if it leads to a treatment change which results in an improved outcome. In practice, however, there are very limited data available regarding the outcomes consequent on imaging at relapse. 6.3.4.1 Assessment of metastases 6.3.4.1.1 Bone scan and abdominopelvic CT Because BCR after RP or RT precedes clinical metastases by 7 to 8 years on average [855, 922], the diagnostic yield of common imaging techniques (bone scan and abdominopelvic CT) is low in asymptomatic patients [923]. In men with PSA-only relapse after RP the probability of a positive bone scan is < 5%, when the PSA level is < 7 ng/mL [924, 925]. Only 11–14% of patients with BCR after RP have a positive CT [924]. In a series of 132 men with BCR after RP the mean PSA level and PSA velocity associated with a positive CT were 27.4 ng/mL and 1.8 ng/mL/month, respectively [926]. 6.3.4.1.2 Choline PET/CT In two different meta-analyses the combined sensitivities and specificities of choline PET/CT for all sites of recurrence in patients with BCR were 86–89% and 89–93%, respectively [927, 928]. Choline PET/CT may detect multiple bone metastases in patients showing a single metastasis on bone scan [929] and may be positive for bone metastases in up to 15% of patients with BCR after RP and negative bone scan [930]. The specificity of choline PET/CT is also higher than bone scan with fewer falsepositive and indeterminate findings [401]. Detection of LN metastases using choline PET/CT remains limited by the relatively poor sensitivity of the technique (see Section 5.3.2.3). Choline PET/CT sensitivity is strongly dependent on the PSA level and kinetics [409, 931, 932]. In patients with BCR after RP, PET/CT detection rates are only 5–24% when the PSA level is < 1 ng/mL but rises to 67–100% when the PSA level is > 5 ng/mL. Despite its limitations, choline PET/CT may change medical management in 18–48% of patients with BCR after primary treatment [933-935]. Choline PET/CT should only be recommended in patients fit enough for curative loco-regional salvage treatment. The sensitivity of choline PET is known to be strongly influenced by PSA level and kinetics and drops to sub-optimal values in patients with a low PSA [932]; after RP a possible PSA cut-off level for choline PET/CT analysis seems to be between 1 and 2 ng/mL [932]. 6.3.4.1.3 Fluoride PET and PET/CT 18F-NaF PET/CT has a higher sensitivity than bone scan in detecting bone metastases [936]. However, 18F-NaF PET is limited by a relative lack of specificity and by the fact that it does not assess soft-tissue metastases [937]. 6.3.4.1.4 Fluciclovine PET/CT PET/CT has a slightly higher sensitivity than choline PET/CT in detecting the site of relapse in BCR [938]. In a recent multi-centre trial evaluating 596 patients with BCR in a mixed population (33.3% after RP, 59.5% after RT ± RP, 7.1% other) fluciclovine PET/CT showed an overall detection rate of 67.7%, with a sensitivity of 62.7% (95% CI: 56–69%); lesions could be visualised either at local level (38.7%) or in LNs and bones (9%) [939]. As for choline PET/CT, fluciclovine PET/CT sensitivity is dependent on the PSA level, with a sensitivity likely inferior to 50% at PSA < 1 ng/mL. A retrospective study investigated 18F-fluciclovine PET/CT and pelvic MRI for PCa at PSA relapse after initial treatment. In the examined cohort of 129 patients 18F-Fluciclovine PET/CT and pelvic MRI demonstrated a high degree of concordance (~94%). The sensitivity, specificity, PPV and NPV for 18F-fluciclovine PET/CT and MRI were 96.6%, 94.3%, 93.4%, and 97%, and 91.5%, 95.7%, 94.7%, and 93%, 18F-Fluciclovine

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respectively, demonstrating similar diagnostic performance between the two modalities [940]. 18F-fluciclovine has been approved in the U.S. and Europe and it is therefore the only PCa-specific radiotracer widely commercially available. 6.3.4.1.5 Prostate-specific membrane antigen based PET/CT Prostate-specific membrane antigen PET/CT has shown good potential in patients with BCR, although most studies are limited by their retrospective design. Reported predictors of 68Ga-PSMA PET in the recurrence setting were recently updated based on a high-volume series (see Table 6.3.1) [397]. Positivity rates in the prostate bed were significantly different in patients after RP (22%) and RT (52%). High sensitivity (75%) and specificity (99%) were observed on per-lesion analysis. Table 6.3.1: PSMA-positivity separated by PSA level category [397] PSA (ng/mL) < 0.2 02–0.49 0.5–0.99 1.0–1.99 2.0+

68Ga-PMSA

PET positivity 33% (CI: 16–51) 45% (CI: 39–52) 59% (CI: 50–68) 75% (CI: 66–84) 95% (CI: 92–97)

PSA = prostate-specific antigen; 68Ga-PSMA PET = Gallium-68 prostate-specific membrane antigen positron emission tomography. Prostate-specific membrane antigen PET/CT seems substantially more sensitive than choline PET/CT, especially for PSA levels < 1 ng/mL [941, 942]. In a study of 314 patients with BCR after treatment and a median PSA level of 0.83 ng/mL, 68Ga-PSMA PET/CT was positive in 197 patients (67%). Of the 88 patients with negative choline PET/CT, 59 (67%) were positive on 68Ga-PSMA PET/CT [943]. In another prospective multi-centre trial including 635 patients with BCR after RP (41%), RT (27%), or both (32%), PPV for 68Ga-PSMA PET/CT was 0.84 (95% CI: 0.75–0.90) by histopathologic validation (primary endpoint, n = 87) and 0.92 (95% CI: 0.75–0.90) by a composite reference standard. Detection rates significantly increased with PSA, from 38% for PSA < 0.5 ng/mL (n = 136) to 57% for PSA of 0.5–1.0 ng/mL (n = 79), 84% for PSA of 1.0–2.0 ng/mL (n = 89), 86% for PSA of 2.0–5.0 ng/mL (n = 158), and 97% for PSA > 5.0 ng/mL (n = 173, p < 0.001) [944]. It is worth noting that the term ‘PSMA PET’ refers to several different radiopharmaceuticals; the majority of published studies used 68Ga-PSMA-11 [397, 895, 897, 945, 946], but other authors are reporting data with 18F-labelled PSMA [898, 899]. At present there are no conclusive data about comparison of such tracers [947]. 6.3.4.1.6 Whole-body and axial MRI Little is known regarding the accuracy of whole-body or axial MRI in patients with BCR after RP or RT [948]. Therefore, the role of these techniques in detecting occult bone or LN metastases in the case of BCR requires further assessment. 6.3.4.2 Assessment of local recurrences 6.3.4.2.1 Local recurrence after radical prostatectomy Because the sensitivity of anastomotic biopsies is low, especially for PSA levels < 1 ng/mL [923], salvage RT is usually decided on the basis of BCR without histological proof of local recurrence. The dose delivered to the prostatic fossa tends to be uniform since it has not been demonstrated that a focal dose escalation at the site of recurrence improves the outcome. Therefore, most patients undergo salvage RT without local imaging. Magnetic resonance imaging can detect local recurrences in the prostatic bed but its sensitivity in patients with a PSA level < 0.5 ng/mL remains controversial [949, 950]. Choline PET/CT is less sensitive than MRI when the PSA level is < 1 ng/mL [951]. In a retrospective study of 53 patients with BCR after RP (median PSA level 1.5 ng/mL) who underwent 18F-choline whole body hybrid PET/MRI, MRI identified more local relapses (17 vs. 14, p = 0.453) while PET outperformed whole-body MRI for detection of regional (16 vs. 9, p = 0.016) and distant (12 vs. 6, p = 0.031) metastases [952]. The detection rates of 68Ga-PSMA PET/CT in patients with BCR after RP are 11.3–50% for PSA levels < 0.2 ng/mL, 20–72% for PSA levels of 0.20–0.49 ng/mL and 25–87.5% for PSA levels of 0.5–1 ng/mL [953]. Prostate-specific membrane antigen PET/CT sudies showed that a substantial part of recurrences after RP were located outside the prostatic fossa even at low PSA levels. In a retrospective study of 125 patients with a median PSA level of 0.40 ng/mL (interquartile range 0.28–0.63), PSMA-expressing disease was found in

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66 patients (53%), of whom 25 patients (38%) had PSMA-avid lesions outside the pelvis, 33 (50%) had lesions confined to the pelvic LNs and prostate bed, and 8 (12%) had recurrence only in the prostate fossa [954]. In another retrospective study of 119 men with a mean PSA level of 0.34 ng/mL, 68Ga-PSMA PET/CT was positive in 41 patients (34.4%); only 3 were positive in the prostatic fossa, while 21 had uptake in the skeleton, 4 in retroperitoneal LNs and 21 in pelvic LNs [895]. Combining 68Ga-PSMA PET and MRI may improve the detection of local recurrences, as compared to 68Ga-PSMA PET/CT [955]. 6.3.4.2.2 Local recurrence after radiation therapy In patients with BCR after RT biopsy status is a major predictor of outcome, provided the biopsies are obtained 18–24 months after initial treatment. Given the morbidity of local salvage options it is necessary to obtain histological proof of the local recurrence before treating the patient [923]. Transrectal US is not reliable in identifying local recurrence after RT. In contrast, MRI has yielded excellent results and can be used for biopsy targeting and guiding local salvage treatment [923, 956-959], even if it slightly underestimates the volume of the local recurrence [960]. Detection of recurrent cancer is also feasible with choline PET/CT [961], but choline PET/CT has not yet been compared to mpMRI. Prostatespecific membrane antigen PET/CT can also play a role in the detection of local recurrences after RT [397]. 6.3.4.3 Summary of evidence on imaging in case of biochemical recurrence In patients with BCR imaging can detect both local recurences and distant metastases, however, the sensitivity of detection depends on the PSA level. After RP, PSMA PET/CT seems to be the imaging modality with the highest sensitivity at low PSA levels (< 0.5 ng/mL) and may help distinguishing patients with recurrences confined to the prostatic fossa from those with distant metastases which may impact the design and use of post-RP salvage RT. After RT, MRI has shown excellent results at detecting local recurrences and guiding prostate biopsy. Given the substantial morbidity of post-RT salvage local treatments, distant metastases must be ruled out in patients with local recurrences and who are fit for these salvage therapies. Choline-, fluciclovine- or PSMA-PET/CT can be used to detect metastases in these patients but for this indication PSMA PET/CT seems the most sensitive technique. 6.3.4.4

Guidelines for imaging in patients with biochemical recurrence

Recommendations Prostate-specific antigen (PSA) recurrence after radical prostatectomy Perform prostate-specific membrane antigen (PSMA) positron emission tomography (PET) computed tomography (CT) if the PSA level is > 0.2 ng/mL and if the results will influence subsequent treatment decisions. In case PSMA PET/CT is not available, and the PSA level is > 1 ng/mL, perform fluciclovine PET/CT or choline PET/CT imaging if the results will influence subsequent treatment decisions. PSA recurrence after radiotherapy Perform prostate magnetic resonance imaging to localise abnormal areas and guide biopsies in patients fit for local salvage therapy. Perform PSMA PET/CT (if available) or fluciclovine PET/CT or choline PET/CT in patients fit for curative salvage treatment.

Strength rating Weak

Weak

Weak Strong

6.3.5 Treatment of PSA-only recurrences The timing and treatment modality for PSA-only recurrences after RP or RT remain a matter of controversy based on the limited evidence. 6.3.5.1 Treatment of PSA-only recurrences after radical prostatectomy 6.3.5.1.1 Salvage radiotherapy for PSA-only recurrence after radical prostatectomy (cTxcN0M0, without PET/ CT) Early SRT provides the possibility of cure for patients with an increasing PSA after RP. Boorjian et al., reported a 75% reduced risk of systemic progression with SRT when comparing 856 SRT patients with 1,801 non-SRT patients [962]. The RAVES and RADICAL trials assessing SRT in post-RP patients with PSA levels exceeding 0.1–0.2 ng/mL showed 5-year freedom from BCR and BCR-free survival rates of 88% [870, 963]. The PSA level at BCR was shown to be prognostic [962]. More than 60% of patients who are treated before the PSA level rises to > 0.5 ng/mL will achieve an undetectable PSA level [964967], corresponding to a ~80% chance of being progression-free 5 years later [968]. A retrospective analysis of 635 patients who were followed after RP and experienced BCR and/or local recurrence and either received no salvage treatment (n = 397) or salvage RT alone (n = 160) within 2 years of BCR

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showed that salvage RT was associated with a 3-fold increase in PCa-specific survival relative to those who received no salvage treatment (p < 0.001). Salvage RT has been shown to be effective mainly in patients with a short PSA-DT [969]. According to a Panel systematic review which also proposed a scoring system [916], men with a PSA-DT > 1 year and a pathological GS < 8 have a significantly lower risk of clinical progression and can be classified as ‘EAU Low Risk’; men with a PSA-DT < 1 year or a pathological pGS 8–10 are at increased risk of clinical progression and should be classified as ‘EAU High Risk’. These definitions have been externally validated and may be helpful for individualised treatment decisions [921]. Despite the indication for salvage RT, a ‘wait and see‘ strategy remains an option in patients with a PSA-DT of more than 12 months and other favourable factors such a time to BCR > 3 years, < pT3a, ISUP grade < 2/3 [916, 970]. For an overview see Table 6.3.2. Although biochemical progression is now widely accepted as a surrogate marker of PCa recurrence; metastatic disease, disease-specific and OS are more meaningful endpoints to support clinical decision-making. A systematic review and meta-analysis on the impact of BCR after RP reports SRT to be favourable for OS and PCa-specific mortality. In particular SRT should be initiated in patients with rapid PSA kinetics after RP and with a PSA cut-off of 0.4 ng/mL [916]. A recent international multi-institutional analysis of pooled data from RCTs has suggested that metastasis-free survival is the most valid surrogate endpoint with respect to impact on OS [971, 972]. Table 6.3.3 summarises results of recent studies on clinical endpoints after SRT. Table 6.3.2: S  elected studies of post-prostatectomy salvage radiotherapy, stratified by pre-salvage radiotherapy PSA level* (cTxcN0M0, without PET/CT) RT dose ADT

bNED/PFS (year)

5-yr. results

71

pre-SRT PSA (ng/mL) median 0.31

66.6 Gy

54% (5.9)

36

< 1 (58%)

68 Gy 24% ADT 68 Gy 16% ADT

63/55% (3) ADT/no ADT 50% (5) 36% (10)

66 Gy 16% ADT

56% (5)

73% vs. 56%; PSA < 0.2 vs. > 0.2 ng/mL p < 0.0001 44/40% ADT/no ADT p < 0.16 44% vs. 58%; PSA < 0.5 vs. > 0.5 ng/mL p < 0.001 SRT; PSA < 0.2 ng/mL 71% 0.21-0.5 ng/mL 63% 0.51-1.0 ng/mL 54% 1.01-2.0 ng/mL 43% > 2 ng/mL 37% p < 0.001

Reference

n

Median FU (mo)

Bartkowiak, et al. 2018 [973] Soto, et al. 2012 [974] Stish, et al. 2016 [964]

464

441

1,106 107

0.6

Tendulkar, et al. 2016 [975]

2,460 60

0.5

*Androgen deprivation therapy can influence the outcome ‘biochemically no evidence of disease (bNED)’ or ‘progression-free survival’. To facilitate comparisons, 5-year bNED/PFS read-outs from Kaplan-Meier plots are included. ADT = androgen deprivation therapy; bNED = biochemically no evidence of disease; FU = follow up; mo = months; n = number of patients; PFS = progression-free survival; PSA = prostate-specific antigen; SRT = salvage radiotherapy; yr = year. Table 6.3.3: R  ecent studies reporting clinical endpoints after SRT (cTxcN0M0, without PET/CT) (the majority of included patients did not receive ADT) Reference

n

Bartkowiak, et al. 2018 [973]

464

92

Median FU Regimen (mo) 71 66.6 (59.4-72) Gy no ADT

Outcome 5.9 yr. OS post-SRT PSA < 0.1 ng/mL 98% post-SRT PSA > 0.1 ng/mL 92% p = 0.005

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Jackson, et al. 2014 [976]

448

64

68.4 Gy no ADT

Stish, et al. 2016 [964]

1,106

107

68 (64.8-70.2) Gy 39% 2D treatment planning incl. 16% ADT

Tendulkar, et al. 2016 [975]

2,460

60

66 (64.8-68.4) Gy incl. 16% ADT

5 yr. DM post-SRT PSA < 0.1 ng/mL 5% post-SRT PSA > 0.1 ng/mL 29% p < 0.0001 5 yr. DSM post-SRT PSA < 0.1 ng/mL 2% post-SRT PSA > 0.1 ng/mL 7% p < 0.0001 OS post-SRT PSA < 0.1 ng/mL 97% post-SRT PSA > 0.1 ng/mL 90% p < 0.0001 5 and 8.9 yr. DM SRT: PSA < 0.5 ng/mL 7% and 12% SRT: PSA > 0.5 ng/mL 14% and 23% p < 0.001 5 and 8.9 yr. DSM SRT: PSA < 0.5 ng/mL < 1% and 6% SRT: PSA > 0.5 ng/mL 5% and 10% p = 0.02 5 and 8.9 yr. OS SRT: PSA < 0.5 ng/mL 94% and 86% SRT: PSA > 0.5 ng/mL 91% and 78% p = 0.14 10 yr. DM SRT: PSA 0.01-0.2 ng/mL 9% SRT: PSA 0.21-0.50 ng/mL 15% SRT: PSA 0.51-1.0 ng/mL 19% SRT: PSA 1.01-2.0 ng/mL 20% SRT: PSA > 2 ng/mL 37%, p < 0.001

ADT = androgen deprivation therapy; DM = distant metastasis; DSM = disease specific mortality; FU = follow up; mo. = month; n = number of patients; OS = overall survival; PSA = prostate specific antigen; SRT = salvage radiotherapy. 6.3.5.1.2 Salvage radiotherapy combined with androgen deprivation therapy (cTxcN0, without PET/CT) Data from RTOG 9601 [977] suggest both CSS and OS benefit when adding 2 years of bicalutamide (150 mg o.d.) to SRT. According to GETUG-AFU 16 also 6-months treatment with a LHRH-analogue can significantly improve 10-year BCR, biochemical PFS and, modestly, metastasis-free survival. However, SRT combined with either goserelin or placebo showed similar DSS and OS rates [978]. Table 6.3.4 provides an overview of these two RCTs. These RCTs support adding ADT to SRT. However when interpreting these data it has to be kept in mind that RTOG 9601 used outdated radiation dosages (< 66 Gy) and technique. The question with respect to the patient risk profile, whether to offer combination treatment or not, and the optimal combination (LHRH or bicalutamide) remains, as yet, unsolved. The EAU risk classification may offer guidance in this respect [916, 921]. One of these RCTs reports improved OS (RTOG 96-01) and the other improved metastasis-free survival but due to methodological discrepancies also related to follow-up and risk patterns, it is, as yet, not evident which patients should receive ADT, which type of ADT and for how long. Men at high risk of further progression (e.g., with a PSA > 0.7 ng/mL and GS > 8) may benefit from SRT combined with two years of ADT; for those at lower risk (e.g., PSA < 0.7 ng/mL and GS 8) SRT combined with 6 months of ADT may be sufficient. Men with a low-risk profile (PSA < 0.5 ng/mL and GS < 8) may receive SRT alone. In a sub-analysis of men with a PSA of 0.61 to 1.5 (n = 253) there was an OS benefit associated with anti-androgen assignment (HR: 0.61, 95% CI: 0.39–0.94). In those receiving early SRT (PSA 0.6 ng/mL, n = 389), there was no improvement in OS (HR: 1.16, 95% CI: 0.79–1.70), an increased other-cause mortablity hazard (subdistribution HR: 1.94, 95% CI: 1.17–3.20, p = 0.01) and increased odds of late grades 3–5 cardiac and neurologic toxic effects (OR: 3.57, 95% CI: 1.09–15.97, p = 0.05). These results suggest that pre-SRT PSA level may be a prognostic biomarker for outcomes of anti-androgen treatment with SRT. In patients receiving late SRT (PSA > 0.6 ng/mL, hormone therapy was associated with improved outcomes. In men receiving early SRT (PSA < 0.6 ng/mL), long-term anti-androgen treatment was not associated with improved OS [979]. A recent review addressing the benefit from combining HT with SRT suggested risk stratification of patients based on the pre-SRT PSA (< 0.5, 0.6–1, > 1 ng/mL), margin status and ISUP grade as a framework

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to individualise treatment [980]. In a retrospective multi-centre-study including 525 patients, only in patients with more aggressive disease characteristics (pT3b/4 and ISUP grade > 4 or pT3b/4 and PSA at early SRT > 0.4 ng/mL) the administration of concomitant ADT was associated with a reduction in distant metastasis [981]. Similarly, in a retrospective analysis of 1,125 patients, stage > pT3b, GS > 8 and a PSA level at SRT > 5 ng/mL were identified as risk factors for clinical recurrence. A significant effect of long-term ADT was observed in patients with > 2 adverse features. For patients with a single risk factor, short-term HT was sufficient whilst patients without risk factors showed no significant benefit from concomitant ADT [982]. Table 6.3.4: R  andomised controlled trials comparing salvage radiotherapy combined with androgen deprivation therapy vs. salvage radiotherapy alone Reference

n

Risk groups

GETUG-AFU 16 2019 [978]

369 RT + ADT 374 RT

ISUP grade < 2/3 89%,

384 RT + ADT 376 RT

ISUP grade > 4 11% cN0 pT2 R1, pT3 cN0

RTOG 9601 2017 [977]

Median Regimen FU (mo) 112 66 Gy + 6 mo. GnRH analogue 6 mo. 66 Gy

156

64.8 Gy + bicalutamide 24 mo. 64.8 Gy + placebo

Outcome 10 yr. PFS 64% p  0.4 ng/mL and ISUP grade, < 1 vs. 2/3 vs. > 4 [993]. The updated Stephenson nomograms incorporate the SRT and ADT doses as predictive factors for biochemical failure and distant metastasis [975]. Salvage RT is also associated with toxicity. In one report on 464 SRT patients receiving median 66.6 (max. 72) Gy, acute grade 2 toxicity was recorded in 4.7% for both the GI and GU tract. Two men had late grade 3 reactions of the GI tract. Severe GU tract toxicity was not observed. Late grade 2 complications occurred in 4.7% (GI tract) and 4.1% (GU tract), respectively, and 4.5% of the patients developed moderate urethral stricture [973]. In a RCT on dose escalation for SRT involving 350 patients, acute grade 2 and 3 GU toxicity was observed in 13.0% and 0.6%, respectively, with 64 Gy and in 16.6% and 1.7%, respectively, with 70 Gy.

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Gastrointestinal tract toxicity of grades 2 and 3 occurred in 16.0% and 0.6%, respectively, with 64 Gy, and in 15.4% and 2.3%, respectively, with 70 Gy. Late effects have yet to be reported [994, 995]. With dose escalation over 72 Gy and/or up to a median of 76 Gy, the rate of severe side effects, especially genitourinary symptoms, clearly increases, even with newer planning and treatment techniques [996, 997]. In particular, when compared with 3D-CRT, IMRT was associated with a reduction in grade 2 GI toxicity from 10.2 to 1.9% (p = 0.02) but had no differential effect on the relatively high level of GU toxicity (5-year, 3D-CRT 15.8% vs. IMRT 16.8%) [996]. After a median salvage IMRT dose of 76 Gy, the 5-year risk of grade 2–3 toxicity rose to 22% for GU and 8% for GI symptoms, respectively [997]. Doses of at least 66 Gy and up to 72 Gy can be recommended [973, 994]. 6.3.5.1.2.2 Salvage RT with or without ADT (cTx CN0/1) (with PET/CT) In a prospective multi-centre study of 323 patients with BCR, PSMA PET/CT changed the management intent in 62% of patients as compared to conventional staging. This was due to a significant reduction in the number of men in whom the site of disease recurrence was unknown (77% vs. 19%, p < 0.001) and a significant increase in the number of men with metastatic disease (11% vs. 57%) [415]. A recent prospective study in a subgroup of 119 BCR patients with low PSA (< 0.5 ng/mL) reported a change in the intended treatment in 30.2% of patients [895]; however, no data exist on the impact on final outcome. Another prospective study in 272 patients with early biochemical recurrent PCa after RP showed that 68Ga-PSMA-ligand PET/CT may tailor further therapy decisions (e.g., local vs. systemic treatment) at low PSA values (0.2–1 ng/mL) [897]. A single-centre study retrospectively assessed 164 men from a prospective database who underwent imaging with PSMA PET/CT for a rising PSA after RP with PSA levels < 0.5 ng/mL. In men with a negative PSMA PET/CT who received salvage RT, 85% (23 out of 27) demonstrated a treatment response compared to a further PSA increase in 65% of those not treated (22 out of 34). In the 36/99 men with disease confined to the prostate fossa on PSMA, 83% (29 out of 36) responded to salvage RT [945]. Thus, PSMA PET/CT might stratify men into a group with high response (negative findings or recurrence confined to the prostate) and poor response (positive nodes or distant disease) to salvage RT. As there are no prospective phase III data (in particular not for PCa-specific survival or OS) these results have to be confirmed before a recommendation can be provided. 6.3.5.1.2.3 Metastasis-directed therapy for rcN+ (with PET/CT) Radiolabelled PSMA PET/CT is increasingly used as a diagnostic tool to assess metastatic disease burden in patients with BCR following prior definitive therapy. A review including 30 studies and 4,476 patients showed overall estimates of positivity in a restaging setting of 38% in pelvic LNs and 13% in extra-pelvic LN metastases [397]. The percentage positivity of PSMA PET/CT was proven to increase with higher PSA values, from 33% (95% CI: 16–51) for a PSA of < 0.2 ng/mL, to 45% (39–52), 59% (50–68), 75% (66–84), and 95% (92–97) for PSA subgroup values of 0.2–0.49, 0.5–0.99, 1.00–1.99, and > 2.00 ng/mL, respectively [397]. Results of this review demonstrated high sensitivity and specificity of 68Ga-PSMA PET in advanced PCa with a per-lesion-analised sensitivity and specificity of 75% and 99%, respectively. In patients relapsing after a local treatment (including cN+ and higly selected M1 patients), a metastasestargeting therapy has been proposed, with the aim to delay systemic treatment. Metastasis-directed (MDT) therapy in PET/CT detected nodal oligo-recurrent PCa after RP was assessed in a large retrospective multiinstitutional study (263 patients received MDT and 1,816 patients standard of care as control group [matched 3:1]). Metastasis-targeting therapy consisted of salvage LN resection (n = 166) and stereotactic ablation RT (SABR) (n = 97). After a median follow-up of 70 months, the MDT-group showed significantly better CSS (5-year survival 98.6% vs. 95.7%, p < 0.01, respectively) [998]. Another retrospective study compared SABR with elective nodal irradiation (ENRT) in PET/CT-detected nodal oligo-recurrent PCa (n = 506 patients, 365 of which with N1 pelvic recurrence). With a median follow-up of 36 months, ENRT (n = 197) was associated with a significant reduction of nodal recurrences compared with SABR (n = 309) of 2% vs. 18%, respectively, but at the cost of higher side effects of ENRT [999]. These results have to be confirmed in prospective trials before any recommendations can be made. In these situations SABR should be used in highly selected patients only. For MDT in M1-patients see Section 6.4.8. 6.3.5.1.3 Salvage lymph node dissection The surgical management of (recurrent) nodal metastases in the pelvis has been the topic of several retrospective analyses [1000-1002] and a systematic review [1003]. The reported 5-year BCR-free survival rates ranged from 6% to 31%. Five-year OS was approximately 84% [1003]. Biochemical recurrence rates were found to be dependent on PSA at surgery and location and number of positive nodes [1004]. Addition of RT to the lymphatic template after salvage LN dissection may improve the BCR rate [1005]. In a recent multi-centre

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retrospective study long-term outcomes of salvage LN dissection were reported to be worse than previously described in studies with shorter follow-up [1006]. Biochemical recurrence-free survival at 10 years was 11%. Patients with a PSA response after salvage LN dissection and patients receiving ADT within 6 months from salvage LN dissection had a lower risk of death from PCa [1006]. High level evidence for the oncological value of salvage LN dissection is still lacking [1003]. 6.3.5.1.4 Comparison of adjuvant- and salvage radiotherapy Section 6.2.5.4 - ART, is referred to for more details. Main findings are that after RP the vast majority of patients do not need ART which is supported by the results of 3 phase III RCTs comparing adjuvant RT and early salvage RT with a median follow-up of 5 years [870-874]. However, longer term (10-year) results and results of metastasis-free survival endpoints are needed before final conclusions can be drawn. Due to the small number of patients with a combination of high-risk features included in these 3 trails (only approximately 20%) ART remains a recommended treatment option in highly selected patients with at least two out of three high-risk features, such as pT3/R1/ISUP > 3 [854, 874]. 6.3.5.2 Management of PSA failures after radiation therapy Therapeutic options in these patients are ADT or salvage local procedures. A recent systematic review and meta-analysis included all studies comparing the efficacy and toxicity of salvage RP, salvage HIFU, salvage cryotherapy, SBRT, salvage LDR brachytherapy, and salvage HDR brachytherapy in the management of locally recurrent PCa after primary radical EBRT [1007]. The outcomes were BCR-free survival at 2 and 5 years. No significant differences with regards to recurrence-free survival between these modalities was found [1007]. Five-year recurrence-free survival ranged from 50% after cryotherapy to 60% after HDR brachytherapy and SBRT [1007]. The authors reported that severe GU toxicity exceeded 21% for HIFU and RP, whereas it ranged from 4.2% to 8.1% with re-irradiation. Differences in severe GI toxicity also appeared to favour re-irradiation, particularly HDR brachytherapy [1007]. Due to the methodological limitations of this review (the majority of the included studies were uncontrolled single-arm case series and there was considerable heterogeneity in the definitions of core outcomes) the available evidence for these treatment options is of low quality and strong recommendations regarding the choice of any of these techniques cannot be made. The following is an overview of the most important findings for each of these techniques. 6.3.5.2.1 Salvage radical prostatectomy Salvage RP after RT is associated with a higher likelihood of adverse events compared to primary surgery because of the risk of fibrosis and poor wound healing due to radiation [1008]. 6.3.5.2.1.1 Oncological outcomes In a systematic review of the literature, Chade, et al., showed that SRP provided 5- and 10-year BCR-free survival estimates ranging from 47–82% and from 28-53%, respectively. The 10-year CSS and OS rates ranged from 70–83% and from 54–89%, respectively. The pre-SRP PSA value and prostate biopsy ISUP grade were the strongest predictors of the presence of organ-confined disease, progression, and CSS [1009]. In a recent multi-centre analysis including 414 patients, 5-year BCR-free survival, CSS and OS were 56.7%, 97.7% and 92.1%, respectively [1010]. Pathological T stage > T3b (OR: 2.348) and GS (up to OR 7.183 for GS > 8) were independent predictors for BCR. Table 6.3.5: O  ncological results of selected salvage radical prostatectomy case series BCR-free CSS probability (%) (%) 37 83

Time probability

25

Lymph-node involvement (%) 16

50

27

22

49

89

5 yr.

14

50

17

8

85*

-

14 mo.

36

46

30

16

57

98

5 yr.

Pathologic Organconfined (%) 55

PSM (%)

404

Median FU (mo) 55

55

36

96 414

Reference

n

Chade, et al. 2011 [1011] Mandel, et al. 2016 [1012] Ogaya-Pinies, et al. 2018 [1013] Marra, et al. 2021 [1010]

10 yr.

*Percentage of patients without BCR. BCR = biochemical recurrence; CSS = cancer-specific survival; FU = follow-up; mo = months; n = number of patients; PSM = positive surgical margin.

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6.3.5.2.1.2 Morbidity Compared to primary open RP, SRP is associated with a higher risk of later anastomotic stricture (47 vs. 5.8%), urinary retention (25.3% vs. 3.5%), urinary fistula (4.1% vs. 0.06%), abscess (3.2% vs. 0.7%) and rectal injury (9.2 vs. 0.6%) [1014]. In more recent series, these complications appear to be less common [1008, 1009, 1012]. Functional outcomes are also worse compared to primary surgery, with urinary incontinence ranging from 21% to 90% and ED in nearly all patients [1009, 1012]. Table 6.3.6: P  eri-operative morbidity in selected salvage radical prostatectomy case series Reference

n

Ward, et al. 2005 [1015] Sanderson, et al. 2006 [1016] Gotto, et al. 2010 [1014] Gontero, et al. 2019 [1008]

138 51 98 395

Rectal injury (%) Anastomotic stricture (%) 5 22 2 41 9 41 1.6 25

Clavien 3-5 (%) 6 25 3.6

Blood loss, mL, mean, range 10.1

n = number of patients. 6.3.5.2.1.3 Summary of salvage radical prostatectomy In general, SRP should be considered only in patients with low co-morbidity, a life expectancy of at least 10 years, a pre-SRP PSA < 10 ng/mL and initial biopsy ISUP grade < 2/3, no LN involvement or evidence of distant metastatic disease pre-SRP, and those whose initial clinical staging was T1 or T2 [1009]. A meta-analysis and systematic review of local salvage therapies after RT for PCa has suggested that re-irradiation with SBRT, HDR brachytherapy or LDR brachytherapy appears to result in less severe GU toxicity than RP, and re-irradiation with HDR brachytherapy in less severe GI toxicity than RP [1007]. Salvage RP might be associated with more severe GU and GI toxicity compared to re-irradiation [1007]. 6.3.5.2.2 Salvage cryoablation of the prostate 6.3.5.2.2.1 Oncological outcomes Salvage cryoablation of the prostate (SCAP) has been proposed as an alternative to salvage RP, as it has a potentially lower risk of morbidity and equal efficacy. In a recent systematic review a total of 32 studies assessed SCAP, recruiting a total of 5,513 patients. The overwhelming majority of patients (93%) received whole-gland SCAP. The adjusted pooled analysis for 2-year BCR-free survival for SCAP was 67.49% (95% CI: 61.68–72.81%), and for 5-year BCR-free survival was 50.25% (95% CI: 44.10–56.40%). However, the certainty of the evidence was low. Table 6.3.7 summarises the results of a selection of the largest series on SCAP to date in relation to oncological outcomes (BCR only) [1007]. Table 6.3.7: O  ncological results of selected salvage cryoablation of the prostate case series, including at least 250 patients Reference

n

Ginsburg, et al. 2017 [1017] Spiess, et al. 2010 [1018] Li, et al. 2015 [1019] Kovac, et al. 2016 [1020]

898 450 486 486

Median Time point FU (mo) of outcome measurement (yr) 19.0 5 40.8 3.4 18.2 5 18.2 5

Ahmad, et al. 2013 [1021]

283

23.9

3

Pisters, et al. 2008 [1022]

279

21.6

5

BCR-free probability

Definition of failure

71.3% 39.6% 63.8% 75.5% (nadir PSA < 0.4 ng/mL); 22.1% (nadir PSA > 0.4 ng/mL) 67.0% (nadir PSA < 1 ng/mL); 14.0% (nadir PSA > 1 ng/mL) 58.9% (ASTRO); 54.5% (Phoenix)

Phoenix criteria PSA > 0.5 ng/mL Phoenix criteria Phoenix criteria

Phoenix criteria

ASTRO and Phoenix criteria

ASTRO = American Society for Therapeutic Radiology and Oncology; BCR = biochemical recurrence; FU = follow-up; mo. = months; n = number of patients; PSA = prostate-specific antigen; yr. = year.

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6.3.5.2.2.2 Morbidity The main adverse effects and complications relating to SCAP include urinary incontinence, urinary retention due to bladder outflow obstruction, recto-urethral fistula, and erectile dysfunction. The recent SR and meta-analysis [1007] showed an adjusted pooled analysis for severe GU toxicity for SCAP of 15.44% (95% CI: 10.15–21.54%). As before, the certainty of the evidence was low. Table 6.3.8 summarises the results of a selection of the largest series on SCAP to date in relation to GU outcomes. Table 6.3.8: P  eri-operative morbidity, erectile function and urinary incontinence in selected salvage cryoablation case series, including at least 100 patients Study

n

Li, et al. 2015 [1019] Ahmad, et al. 2013 [1021] Pisters, et al. 2008 [1022] Cespedes, et al. 1997 [1023] Chin, et al. 2001 [1024]

486 283 279 143 118

Time point of outcome measurement (mo) 12 12 12 Median 27.0 Median 18.6

Incontinence Obstruction/ Rectourethral ED (%) (%) Retention (%) fistula (%)

33.3 12.0 4.4 28.0 6.7

21.7 8.1 3.2 14.0 NA

4.7 1.8 1.2 NA 3.3

71.3 83.0 NA NA NA

ED = erectile dysfunction; mo = months; n = number of patients. 6.3.5.2.2.3 Summary of salvage cryoablation of the prostate In general, the evidence base relating to the use of SCAP is poor, with significant uncertainties relating to longterm oncological outcomes, and SCAP appears to be associated with significant morbidity. Consequently, SCAP should only be performed in selected patients in experienced centres as part of a clinical trial or welldesigned prospective cohort study. 6.3.5.2.3 Salvage re-irradiation 6.3.5.2.3.1 Salvage brachytherapy for radiotherapy failure Carefully selected patients with a good PS, primary localised PCa, good urinary function and histologically proven local recurrence are candidates for salvage brachytherapy using either HDR- or LDR. In a recent systematic review a total of 16 studies (4 prospective) and 32 studies (2 prospective) assessed salvage HDR and LDR brachytherapy, respectively [1007] with the majority (> 85%) receiving wholegland brachytherapy rather than focal treatment. The adjusted pooled analysis for 2-year BCR-free survival for HDR was 77% (95% CI: 70–83%) and for LDR was 81% (95% CI:74–86%). The 5-year BCR-free survival for HDR was 60% (95% CI: 52–67%) and for LDR was 56% (95% CI: 48–63%). As noted above, brachytherapy techniques are associated with lower rates of severe GU toxicity when compared to RP or HIFU, at 8% for HDR (95% CI: 5.1–11%) and 8.1% for LDR (95% CI: 4.3–13%). Rates of severe GI toxicity are reported to be very low at 0% for HDR (95% CI: 0–0.2%) and 1.5% for LDR (95% CI: 0.2–3.4%). High-dose-rate or LDR brachytherapy are effective treatment options with an acceptable toxicity profile. However, the published series are small and likely under-report toxicity. Consequently this treatment should be offered in experienced centres ideally within randomised clinical trials or prospective registry studies. Table 6.3.9: T  reatment-related toxicity and BCR-free probablity in selected salvage brachytherapy studies including at least 100 patients. Author

Study design

Lopez, et al. 2019 [1025] Crook, et al. 2019 [1026] Smith, et al. 2020 [1027] Lyczek, et al. 2009 [1028]

multi-centre retrospective multi-centre prospective single-centre retrospective single-centre retrospective

n and BT type Median FU Treatment toxicity (mo) 75 HDR 52 23.5% late G3+ GU 44 LDR 100 LDR 54 14% late G3 combined GI/GU 108 LDR 76 15.7%/2.8% late G3 GU/GI 115 HDR n.r. 12.2%/0.9% late G3+ GU/GI

BCR-free probability 5 yr 71% (95% CI: 65.9-75.9%) n.r. 5 yr. 63.1% 10 yr. 52% 60% at 40 mo.

BT = brachytherapy; GI = gastrointestinal; GU = genito-urinary; HDR = high-dose rate; LDR = low-dose rate; mo = months; n = number of patients; n.r. = not reported; yr = year.

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6.3.5.2.3.2 Salvage stereotactic ablative body radiotherapy for radiotherapy failure 6.3.5.2.3.2.1 Oncological outcomes and morbidity Stereotactic ablative body radiotherapy (CyberKnife or Linac-based treatment) is a potentially viable new option to treat local recurrence after RT. Carefully selected patients with good IPSS-score, without obstruction, good PS and histologically proven localised local recurrence are potential candidates for SABR. In a recent meta-analysis and systematic review five mostly retrospective studies including 206 patients were treated with CyberKnife or linac-based-treatment showing 2-year RFS estimates (61.6%, 95% CI: 52.6–69.9%) [1007]. In a retrospective multi-centre study (n = 100) the median pre-salvage PSA was 4.3 ng/mL with 34% of patients having received ADT for twelve months (median). All recurrences were biopsy proven. Patients were treated with the CyberKnife with a single dose of 6 Gy in six daily fractions (total dose 36 Gy). With a median follow-up of 30 months the estimated 3-year second BCR-free survival was 55% [1029]. In a smaller retrospective series including 50 men with histologically proven local recurrence with a median pre-salvage PSA of 3.9 ng/mL only 15% had received additional ADT. The estimated 5-year second BCR-free survival was 60% (median follow-up of 44 months) which is an outcome comparable to series treating patients with RP, HIFU or brachytherapy [1030]. Table 6.3.10 summarises the results of the two larger SABR series addressing oncological outcomes and morbidity. Table 6.3.10: T  reatment-related toxicity and BCR-free survival in selected SABR studies including at least 50 patients Author

Study design

Fuller, et al. 2020 [1030] Pasquier, et al. 2020 [1029]

single-centre retrospective multi-centre retrospective

n and RT-type 50 Cyber Knife 100 Cyber Knife

Median Fractionation ADT FU (mo) (SD/TD) 44 SD 6.8 Gy 7/50 TD 34 Gy 30 SD 6 Gy 34/100 TD 36 Gy median 12 mo.

Treatment toxicity 5 yr: 8% late G3+ GU 3 yr. grade 2+ GU 20.8% GI 1%

BCR-free survival 5 yr. 60% 3 yr. 55%

BCR = biochemical recurrence-free; FU = follow-up; mo = months; n = number of patients; RT-type = type of radiotherapy; SD = single dose; TD = total dose; yr = year. 6.3.5.2.3.2.2 Morbidity In a retrospective single-centre study with 50 consecutive patients chronic significant toxicity was only seen for the GU domain with 5-year grade 2+ and grade 3+ GU rates of 17% and 8%, respectively. No GI toxicity > grade 1 was seen. Of note, of the fifteen patients who were sexually potent pre-salvage SBRT, twelve subsequently lost potency [1030]. In a retrospective French (GETUG) multi-centre series (n = 100) the 3-year late grade 2+ GU and GI toxicity was 20.8% (95% CI: 13–29%) and 1% (95% CI: 0.1–5.1%), respectively [1029]. 6.3.5.2.3.2.3 Summary of salvage stereotactic ablative body radiotherapy Despite the encouraging results so far the number of patients treated with SABR is relatively limited. In view of the rates of higher grade 2+ GU side effects, SABR should only be offered to selected patients, in experienced centres as part of a clinical trial or well-designed prospective study. 6.3.5.2.4 Salvage high-intensity focused ultrasound 6.3.5.2.4.1 Oncological outcomes Salvage HIFU has emerged as an alternative thermal ablation option for radiation-recurrent PCa. Being relatively newer than SCAP the data for salvage HIFU are even more limited. A recent systematic review and meta-analysis also included salvage HIFU [1007]. A total of 20 studies assessed salvage HIFU, recruiting 1,783 patients. The overwhelming majority of patients (86%) received whole-gland salvage HIFU. The adjusted pooled analysis for 2-year BCR-free survival for salvage HIFU was 54.14% (95% CI: 47.77–60.38%) and for 5-year BCR-free survival 52.72% (95% CI: 42.66–62.56%). However, the certainty of the evidence was low. Table 6.3.11 summarises the results of a selection of the largest series on salvage HIFU to date in relation to oncological outcomes (BCR only).

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Table 6.3.11: O  ncological results of selected salvage cryoablation of the prostate case series, including at least 250 patients BCR-free Median Time point probability FU (mo) of outcome measurement (yr) 39.6 5 49.0%

Definition of failure

167

Mean 18.1

3

25.0% (high-risk); 53.0% (low-risk)*

150

35.0

3

48.0%

Phoenix criteria or positive biopsy or initiation of post-HIFU salvage therapy Phoenix criteria

100

12.0

1

50.0%

Study

n

Crouzet, et al. 2017 [1031] Murat, et al. 2009 [1032]

418

Kanthabalan, et al. 2017 [1033] Jones, et al. 2018 [1034]

Phoenix criteria

Nadir PSA > 0.5 ng/mL or positive biopsy

*Results stratified by pre-EBRT D’Amico risk groups BCR = biochemical recurrence; CSS = cancer-specific survival; FU = follow-up; mo = months; n = number of patients; yr = year. 6.3.5.2.4.2 Morbidity The main adverse effects and complications relating to salvage HIFU include urinary incontinence, urinary retention due to bladder outflow obstruction, rectourethral fistula and erectile dysfunction. The recent systematic review and meta-analysis showed an adjusted pooled analysis for severe GU toxicity for salvage HIFU of 22.66% (95% CI: 16.98–28.85%) [1007]. The certainty of the evidence was low. Table 6.3.12 summarises the results of a selection of the largest series on salvage HIFU to date in relation to GU outcomes. Table 6.3.12: P  eri-operative morbidity, erectile function and urinary incontinence in selected salvage HIFU case series, including at least 100 patientss Incontinence* Obstruction/ (%) retention (%)

Rectourethral fistula (%)

ED (%)

418

Time point of outcome measurement (yr) Median 39.6

42.3

18.0

2.3

n.r.

167

Median 18.1

49.5

7.8

3.0

n.r.

150

24

12.5

8.0

2.0

41.7

100

12

42.0

49.0

5.0

74.0

Study

n

Crouzet, et al. 2017 [1031] Murat, et al. 2009 [1032] Kanthabalan, et al. 2017 [1033] Jones, et al. 2018 [1034]

*Incontinence was heterogeneously defined; figures represent at least 1 pad usage. ED = erectile dysfunction; mo = months; n.r. = not reported; n = number of patients. 6.3.5.2.4.3 Summary of salvage high-intensity focused ultrasound There is a lack of high-certainty data which prohibits any recommendations regarding the indications for salvage HIFU in routine clinical practice. There is also a risk of significant morbidity associated with its use in the salvage setting. Consequently, salvage HIFU should only be performed in selected patients in experienced centres as part of a clinical trial or well-designed prospective cohort study. 6.3.6 Hormonal therapy for relapsing patients The Panel conducted a systematic review including studies published from 2000 onwards [1035]. Conflicting results were found on the clinical effectiveness of HT after previous curative therapy of the primary tumour. Some studies reported a favourable effect of HT, including the only RCT addressing the research question of this review (86% vs. 79% advantage in OS in the early HT group) [1036]. Other studies did not find any differences between early vs. delayed, or no, HT. One study found an unfavourable effect of HT [1037]. This may be the result of selecting clinically unfavourable cases for (early) HT and more intensive diagnostic workup and follow-up in these patients. 100

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The studied population is highly heterogeneous regarding their tumour biology and therefore clinical course. Predictive factors for poor outcomes were; CRPC, distant metastases, CSS, OS, short PSA-DT, high ISUP grade, high PSA, increased age and co-morbidities. In some studies, such as the Boorjian, et al. study [970], high-risk patients, mainly defined by a high ISUP grade and a short PSA-DT (most often less than 6 months) seem to benefit most from (early) HT, especially in men with a long life expectancy. No data were found on the effectiveness of different types of HT, although it is unlikely that this will have a significant impact on survival outcomes in this setting. Non-steroidal anti-androgens have been claimed to be inferior compared to castration, but this difference was not seen in M0 patients [969]. One of the included RCTs suggested that intermittent HT is not inferior to continuous HT in terms of OS and CSS [1038]. A small advantage was found in some QoL domains but not overall QoL outcomes. An important limitation of this RCT is the lack of any stratifying criteria such as PSA-DT or initial risk factors. Based on the lack of definitive efficacy and the undoubtedly associated significant side effects, patients with recurrence after primary curative therapy should not receive standard HT since only a minority of them will progress to metastases or PCarelated death. The objective of HT should be to improve OS, postpone distant metastases, and improve QoL. Biochemical response to only HT holds no clinical benefit for a patient. For older patients and those with co-morbidities the side effects of HT may even decrease life expectancy; in particular cardiovascular risk factors need to be considered [1039, 1040]. Early HT should be reserved for those at the highest risk of disease progression defined mainly by a short PSA-DT at relapse (< 6–12 months) or a high initial ISUP grade (> 2/3) and a long life expectancy. 6.3.7 Observation In unselected relapsing patients the median actuarial time to the development of metastasis will be 8 years and the median time from metastasis to death will be a further 5 years [855]. For patients with EAU Low-Risk BCR features (see Section 6.3.3), unfit patients with a life expectancy of less than 10 years or patients unwilling to undergo salvage treatment, active follow-up may represent a viable option. 6.3.8

Guidelines for second-line therapy after treatment with curative intent

Local salvage treatment Recommendations for biochemical recurrence (BCR) after radical prostatectomy Offer monitoring, including prostate-specific antigen (PSA), to EAU Low-Risk BCR patients. Offer early salvage intensity-modulated radiotherapy plus image-guided radiotherapy to men with two consecutive PSA rises. A negative PET/CT scan should not delay salvage radiotherapy (SRT), if otherwise indicated. Do not wait for a PSA threshold before starting treatment. Once the decision for SRT has been made, SRT (at least 66 Gy) should be given as soon as possible. Offer hormonal therapy in addition to SRT to men with BCR. Recommendations for BCR after radiotherapy Offer monitoring, including PSA to EAU Low-Risk BCR patients. Only offer salvage radical prostatectomy (RP), brachytherapy, high-intensity focused ultrasound, or cryosurgical ablation to highly selected patients with biopsy proven local recurrence within a clinical trial setting or well-designed prospective cohort study undertaken in experienced centres. Salvage RP should only be performed in experienced centres. Recommendations for systemic salvage treatment Do not offer androgen deprivation therapy to M0 patients with a PSA-doubling time > 12 months.

6.4

Strength rating Weak Strong Strong Strong Weak Weak Strong

Weak Strong

Treatment: Metastatic prostate cancer

6.4.1 Introduction All prospective data available rely on the definition of M1 disease based on CT scan and bone scan. The influence on treatment and outcome of newer, more sensitive, imaging has not been assessed yet. 6.4.2 Prognostic factors Median survival of patients with newly diagnosed metastases is approximately 42 months [1041] with ADT alone, however, it is highly variable since the M1 population is heterogeneous. Several prognostic factors for survival have been suggested including the number and location of bone metastases, presence of visceral metastases, ISUP grade, PS status and initial PSA alkaline phosphatase, but only few have been validated [1042-1045].

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‘Volume‘ of disease as a potential predictor was introduced by CHAARTED (Chemo-hormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) [1045-1047] and has been shown to be predictive in a powered subgroup analysis for benefit of addition of prostate radiotherapy ADT [1048]. Based on a large SWOG 9346 cohort, the PSA level after 7 months of ADT was used to create 3 prognostic groups (see Table 6.4.1) [1049]. A PSA < 0.2 ng/mL at 7 months has been confirmed as a prognostic marker for men receiving ADT for metastatic disease in the CHAARTED study independent of the addition of docetaxel [1050]. Table 6.4.1 Definition of high- and low-volume and risk in CHAARTED [1045-1047] and LATITIDE [744]

CHAARTED (volume) LATITUDE (risk)

High > 4 Bone metastasis including > 1 outside vertebral column or pelvis OR Visceral metastasis > 2 high-risk features of: • > 3 Bone metastasis • Visceral metastasis • > ISUP grade 4

Low Not high

Not high

Table 6.4.2: Prognostic factors based on the SWOG 9346 study [1049] PSA after 7 months of castration < 0.2 ng/mL 0.2 < 4 ng/mL > 4 ng/mL

Median survival on ADT monotherapy 75 months 44 months 13 months

6.4.3 First-line hormonal treatment Primary ADT has been the standard of care for over 50 years [709]. There is no high level evidence in favour of a specific type of ADT, neither for orchiectomy or for an LHRH analogue or antagonist, with the exception of patients with impending spinal cord compression for whom either a bilateral orchidectomy or LHRH antagonists are the preferred options. 6.4.3.1 Non-steroidal anti-androgen monotherapy Based on a Cochrane review comparing non-steroidal anti-androgen (NSAA) monotherapy to castration (either medical or surgical), NSAA was considered to be less effective in terms of OS, clinical progression, treatment failure and treatment discontinuation due to adverse events [1051]. The evidence quality of the studies included in this review was rated as moderate. 6.4.3.2 Intermittent versus continuous androgen deprivation therapy Three independent reviews [1052-1054] and two meta-analyses [1055, 1056] looked at the clinical efficacy of intermittent androgen deprivation (IAD) therapy. All of these reviews included 8 RCTs of which only 3 were conducted in patients with exclusively M1 disease. The 5 remaining trials included different patient groups, mainly locally-advanced and metastatic patients relapsing. So far, the SWOG 9346 is the largest trial addressing IAD in M1b patients [1057]. Out of 3,040 screened patients, only 1,535 patients met the inclusion criteria. This highlights that, at best, only 50% of M1b patients can be expected to be candidates for IAD, i.e. the best PSA responders. This was a non-inferiority trial leading to inconclusive results: the actual upper limit was above the pre-specified 90% upper limit of 1.2 (HR: 1.1, CI: 0.99–1.23), the pre-specified non-inferiority limit was not achieved, and the results did not show a significant inferiority for any treatment arm. However, based on this study inferior survival with IAD cannot be completely ruled out. Other trials did not show any survival difference with an overall HR for OS of 1.02 (0.94–1.11) [1052]. These reviews and the meta-analyses came to the conclusion that a difference in OS or CSS between IAD and continuous ADT is unlikely. A recent review of the available phase III trials highlighted the limitations of most trials and suggested a cautious interpretation of the non-inferiority results [1058]. None of the trials that addressed IAD vs. continuous ADT in M1 patients showed a survival benefit but there was a constant trend towards improved OS and PFS with continuous ADT. However, most of these trials were non-inferiority trials. In

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some cohorts the negative impact on sexual function was less pronounced with IAD. There is a trend favouring IAD in terms of QoL, especially regarding treatment-related side effects such as hot flushes [1059, 1060]. 6.4.3.3 Immediate versus deferred androgen deprivation therapy In symptomatic patients immediate treatment is mandatory, however, controversy still exists for asymptomatic metastatic patients due to the lack of high quality studies. A first Cochrane review extracted four RCTs: the VACURG I and II trials, the MRC trial, and the ECOG 7887 study [1050, 1051]. These studies were conducted in the pre-PSA era and included patients with advanced metastatic or non-metastatic PCa who received immediate vs. deferred ADT [1061]. No improvement in PCa CSS was observed, although immediate ADT significantly reduced disease progression. The Cochrane analysis was updated in 2019 and concluded that early ADT probably extends time to death of any cause and time to death from PCa [1062]. Since the analysis included only a very limited number of M1 patients who were not evaluated separately, the benefit of immediate ADT in this setting remains unclear. 6.4.4 Combination therapies All of the following combination therapies have been studied with continuous ADT, not intermittent ADT. 6.4.4.1 ‘Complete’ androgen blockade The largest RCT in 1,286 M1b patients found no difference between surgical castration with or without flutamide [1063]. However, results with other anti-androgens or castration modalities have differed and systematic reviews have shown that CAB using a NSAA appears to provide a small survival advantage (< 5%) vs. monotherapy (surgical castration or LHRH agonists) [1064, 1065] beyond 5 years of survival [1066] but this minimal advantage in a small subset of patients must be balanced against the increased side effects associated with long-term use of NSAAs. 6.4.4.2 Androgen deprivation combined with other agents 6.4.4.2.1 Androgen deprivation therapy combined with chemotherapy Three large RCTs were conducted [801, 1045, 1067]. All trials compared ADT alone as the standard of care with ADT combined with immediate docetaxel (75 mg/sqm, every 3 weeks within 3 months of ADT initiation). The primary objective in all three studies was to assess OS. The key findings are summarised in Table 6.4.3. Table 6.4.3: Key findings - Hormonal treatment combined with chemotherapy

n Newly diagnosed M+ Key inclusion criteria

Primary objective Median follow up (mo) HR (95% CI)

STAMPEDE [801, 1068] ADT ADT + Docetaxel + P 1,184 592 58% 59%

GETUG [1067] ADT ADT + Docetaxel 193 192 75% 67%

Patients scheduled for longMetastatic disease term ADT Karnofsky score > 70% - newly diagnosed M1 or N+ situations - locally advanced (at least two of cT3 cT4, ISUP grade > 4, PSA > 40 ng/mL) - relapsing locally treated disease with a PSA > 4 ng/mL and a PSA-DT < 6 mo.

CHAARTED [1045,1046] ADT ADT + Docetaxel 393 397 73% 73% Metastatic disease ECOG PS 0, 1 or 2

or PSA > 20 ng/mL, or nodal or metastatic relapse OS

OS

OS

43; 78.2 (update M1)

50

54 (update)

0.78 (0.66-0.93)

1.01 (0.75-1.36)

0.72 (0.59-0.89)

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M1 only n HR (95% CI)

1,086 0.81 (0.69-0.95)

-

-

ADT = androgen deprivation therapy; ECOG = Eastern Cooperative Oncology Group; FU = follow-up; HR = hazard ratio; ISUP = International Society for Urological Pathology; mo = month; n = number of patients; OS = overall survival; P = prednisone; PSA-DT = prostate-specific antigen-doubling time. In the GETUG 15 trial, all patients had newly diagnosed M1 PCa, either de novo or after a primary treatment [1067]. They were stratified based on previous treatment and Glass risk factors [1042]. In the CHAARTED trial the same inclusion criteria applied and patients were stratified according to disease volume; high volume being defined as either presence of visceral metastases or four, or more, bone metastases, with at least one outside the spine and pelvis [1045]. STAMPEDE is a multi-arm multi-stage trial in which the reference arm (ADT monotherapy) included 1,184 patients. One of the experimental arms was docetaxel combined with ADT (n = 593), another was docetaxel combined with zoledronic acid (n = 593). Patients were included with either M1 or N1, or having two of the following 3 criteria: T3/4, PSA > 40 ng/mL or ISUP grade 4–5. Also relapsed patients after local treatment were included if they met one of the following criteria: PSA > 4 ng/mL with a PSA-DT < 6 months or a PSA > 20 ng/mL, N1 or M1. No stratification was used regarding metastatic disease volume (high/low volume) [801]. In all 3 trials toxicity was mainly haematological with around 12–15% grade 3–4 neutropenia, and 6–12% grade 3–4 febrile neutropenia. The use of granulocyte colony-stimulating factor receptor (GCSF) was shown to be beneficial in reducing febrile neutropenia. Primary or secondary prophylaxis with GCSF should be based on available guidelines [1069, 1070]. Based on these data, upfront docetaxel combined with ADT should be considered as a standard in men presenting with metastases at first presentation provided they are fit enough to receive the drug [1070]. Docetaxel is used at the standard dose of 75 mg/sqm combined with steroids as pre-medication. Continuous oral corticosteroid therapy is not mandatory. In subgroup analyses from GETUG-AFU 15 and CHAARTED the beneficial effect of the addition of docetaxel to ADT is most evident in men with de novo metastatic high-volume disease [1046, 1047], while it was in the same range whatever the volume in the post-hoc analysis from STAMPEDE [1068]. The effects were less apparent in men who had prior local treatment although the numbers were small and the event rates lower. A systematic review and meta-analysis which included these 3 trials showed that the addition of docetaxel to standard of care improved survival [1070]. The HR of 0.77 (95% CI: 0.68–0.87, p < 0.0001) translates into an absolute improvement in 4-year survival of 9% (95% CI: 5–14). Docetaxel in addition to standard of care also improves failure-free survival, with a HR of 0.64 (0.58–0.70, p < 0.0001) translating into a reduction in absolute 4-year failure rates of 16% (95% CI: 12–19). 6.4.4.2.2 Combination with the new hormonal treatments (abiraterone, apalutamide, enzalutamide) In two large RCTs (STAMPEDE, LATITUDE) the addition of abiraterone acetate (1000 mg daily) plus prednisone (5 mg daily) to ADT in men with mHSPC was studied [40, 744, 1071]. The primary objective of both trials was an improvement in OS. Both trials showed a significant OS benefit but in LATITUDE in high-risk metastatic patients only with a HR of 0.62 (0.51–0.76) [744]. The HR in STAMPEDE was very similar with 0.63 (0.52–0.76) in the total patient population (metastatic and non-metastatic) and a HR of 0.61 in the subgroup of metastatic patients [40]. The inclusion criteria in the two trials differed but both trials were positive for OS. While only high-risk patients were included in the LATITUDE trial a post-hoc analysis from STAMPEDE showed the same benefit whatever the risk or the volume stratification [1072]. All secondary objectives such as PFS, time to radiographic progression, time to pain, or time to chemotherapy were positive and in favour of the combination. The key findings are summarised in Table 6.4.4. No difference in treatment-related deaths was observed with the combination of ADT plus abiraterone acetate and prednisone compared to ADT monotherapy (HR: 1.37 [0.82–2.29]). However, twice as many patients discontinued treatment due to toxicity in the combination arms in STAMPEDE (20%) compared to LATITUDE (12%). Based on these data upfront abiraterone acetate plus prednisone combined with ADT should be considered as a standard in men presenting with metastases at first presentation, provided they are fit enough to receive the drug (see Table 6.4.4) [1071]. In three large RCTs (ENZAMET, ARCHES and TITAN) the addition of AR antagonists to ADT in men with mHSPC was tested [742, 743, 1073]. In ARCHES the primary endpoint was radiographic progression-free survival (rPFS). Radiographic PFS was significantly improved for the combination of enzalutamide and ADT

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with a HR of 0.39 (0.3–0.5). Approximately 36% of the patients had low-volume disease; around 25% had prior local therapy and 18% of the patients had received prior docetaxel. In ENZAMET the primary endpoint was OS. The addition of enzalutamide to ADT improved OS with a HR of 0.67 (0.52–0.86). Approximately half of the patients had concomitant docetaxel; about 40% had prior local therapy and about half of the patients had lowvolume disease [743]. In the TITAN trial, ADT plus apalutamide was used and rPFS and OS were co-primary endpoints. Radiographic PFS was significantly improved by the addition of apalutamide with a HR of 0.48 (0.39–0.6); OS at 24 months was improved for the combination with a HR of 0.67 (0.51–0.89). In this trial 16% of patients had prior local therapy, 37% had low-volume disease and 11% received prior docetaxel [742]. In summary, the addition of AR antagonists significantly improves clinical outcomes with no convincing evidence of differences between subgroups. The majority of patients treated had de novo metastatic disease and the evidence is most compelling in this situation. In the trials with the AR antagonists, a proportion of patients had metachronous disease (see Table 6.4.5); therefore a combination should also be considered for men progressing after radical local therapy. Lastly, whether the addition of an AR antagonist plus docetaxel adds further OS benefit is currently not observed. Longer follow-up data are needed before a definitive conclusion is possible. At the moment, since toxicity clearly increases, AR antagonists plus docetaxel should not be given outside of clinical trials. Table 6.4.4: Results from the STAMPEDE arm G and LATITUDE studies

n Newly diagnosed N+ Newly diagnosed M+ Key inclusion criteria

Primary objective

STAMPEDE [40] ADT ADT + AA + P 957 960 20% 19% 50% 48% Patients scheduled for long-term ADT - newly diagnosed M1 or N+ situations - locally advanced (at least two of cT3 cT4, ISUP grade > 4, PSA > 40 ng/mL) - relapsing locally treated disease with a PSA > 4 ng/mL and a PSA-DT < 6 mo. or PSA > 20 ng/mL or nodal or metastatic relapse OS

Median follow up (mo) 40 3-yr. OS 83% (ADT + AA + P) 76% (ADT) HR (95% CI) 0.63 (0.52 - 0.76) M1 only n 1,002 3-yr. OS NA HR (95% CI) HR

0.61 (0.49-0.75) FFS (biological, radiological, clinical or death): 0.29 (0.25-0.34)

LATITUDE [744] ADT + placebo ADT + AA + P 597 602 0 0 100% 100% Newly diagnosed M1 disease and 2 out of the 3 risk factors: ISUP grade > 4, > 3 bone lesions, measurable visceral metastasis

OS Radiographic PFS 30.4 66% (ADT + AA + P) 49% (ADT + placebo) 0.62 (0.51-0.76) 1,199 66% (ADT + AA + P) 49% (ADT + placebo) 0.62 (0.51-0.76) Radiographic PFS: 0.49 (0.39-0.53)

AA = abiraterone acetate; ADT = androgen deprivation therapy; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; FFS = failure-free survival; HR = hazard ratio; mo = month; n = number of patients; NA = not available; OS = overall survival; P = prednisone; PFS = progression-free survival; PSA = prostate-specific antigen; yr. = year.

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Table 6.4.5 Results from the ENZAMET and TITAN studies

n Newly diagnosed M+ (ENZAMET incl. unknown) Low volume Primary objective

ENZAMET [1073] ADT+ older antagonist +/-docetaxel (SOC) 562 72.1%

47% OS

TITAN [742] ADT + enzalutamide ADT + placebo +/-docetaxel

ADT + apalutamide

563 72.5%

527 83.7%

525 78.3%

48%

36% 38% OS Radiographic PFS 30.4 2-yr survival: 84% (ADT + apalutamide) 74% (ADT + placebo) 0.67 (0.51-0.89)

Median follow up (mo) 34 3-yr. OS 3-yr survival: 80% (ADT + enzalutamide) 72% (SOC) HR (95% CI) for OS 0.67 (0.52-0.86)

ADT = androgen deprivation therapy; CI = confidence interval; HR = hazard ratio; mo = month; n = number of patients; OS = overall survival; SOC = standard of care; PFS = progression-free survival; yr = year. 6.4.5 Treatment selection and patient selection There are no head-to-head data comparing 6 cycles of docetaxel and the long-term use of abiraterone acetate plus prednisone in newly diagnosed mHSPC. However, for a period, patients in STAMPEDE were randomised to either the addition of abiraterone or docetaxel to standard of care. Data from the two experimental arms has been extracted although this was not pre-specified in the protocol and therefore the data were not powered for this comparison. The survival advantage for both drugs appeared similar [1074]. A recent meta-analysis also found no significant OS benefit for either drug [1075]. Limitations of network meta-analyses include variable patient populations with different treatment benefits and follow-up periods. In the STOPCAP systematic review and meta-analysis, abiraterone acetate plus prednisone was found to have the highest probability of being the most effective treatment [1076]. Both modalities have different and agent-specific side effects and require strict monitoring of side effects during treatment. Therefore, the choice will most likely be driven by patient preference, the specific side effects, fitness for docetaxel, availability and cost. There have been several network meta-analyses of the published data concluding that combination therapy is more efficient than ADT alone, but none of the combination therapies has been clearly proven to be superior over another [1077, 1078]. Life expectancy has to be taken into account when deciding on offering a combination therapy vs. ADT alone. Radiographic PFS is significantly prolonged in all trials for the combination therapies, e.g., from 14.8 months to 33 months in the LATITUDE trial, therefore suggesting that men with a life expectancy below 15 months are not likely to profit clinically from receiving a combination therapy. 6.4.6 Deferred treatment for metastatic PCa (stage M1) The only candidates with metastasised disease who may possibly be considered for deferred treatment are asymptomatic patients with a strong wish to avoid treatment-related side effects. However, since the median survival is only 42 months the time without treatment (before symptoms) is short in most cases. The risk of developing symptoms, and even dying from PCa, without receiving any benefit from hormone treatment has been highlighted [796, 805]. Patients with deferred treatment for advanced PCa must be amenable to close follow-up. 6.4.7 Treatment of the primary tumour in newly diagnosed metastatic disease The first reported trial evaluating prostate RT in men with metastatic castration-sensitive disease was the HORRAD trial. Four hundred and thirty-two patients were randomised to ADT alone or ADT plus IMRT with IGRT to the prostate. Overall survival was not significantly different (HR: 0.9 [0.7-1.14]), median time to PSA progression was significantly improved in the RT arm (HR: 0.78 [0.63–0.97]) [1079]. The STAMPEDE trial evaluated 2,061 men with mCSPC who were randomised to ADT alone vs. ADT plus RT to the prostate. This trial confirmed that RT to the primary tumour did not improve OS in unselected patients [1048]. However, following the results from CHAARTED and prior to analysing the data, the original screening investigations were retrieved and patients categorised as low- or high volume. In the low-volume subgroup (n = 819) there was a significant OS benefit by the addition of prostate RT and it must be highlighted that this benefit was obtained without an increased dose. The doses and template used in STAMPEDE should be considered (55 Gy in 20 daily

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fractions over 4 weeks or 36 Gy in 6-weekly fractions of 6 Gy or a biological equivalent total dose of 72 Gy). Therefore RT of the prostate only in patients with low-volume metastatic disease should be considered. Of note, only 18% of these patients had additional docetaxel and no patients had additional abiraterone acetate plus prednisone, so no clear recommendation can be made about triple combinations. In addition, it is not clear if these data can be extrapolated to RP as local treatment as results of ongoing trials are awaited. In a recent systematic review and meta-analysis including the above two RCTs, the authors found that, overall, there was no evidence that the addition of prostate RT to ADT improved survival in unselected patients (HR: 0.92, 95% CI: 0.81–1.04, p = 0.195) [1080]. However, there was a clear difference in the effect of metastatic burden on survival with an absolute improvement of 7% in 3-year survival in men who had four or fewer bone metastases. 6.4.8 Metastasis-directed therapy in M1-patients In patients relapsing after a local treatment, a metastases-targeting therapy has been proposed, with the aim to delay systemic treatment. There are two randomised phase II trials testing metastasis-directed therapy (MDT) using surgery ± SABR vs. surveillance [1081] or SABR vs. surveillance in men with oligo-recurrent PCa [1082]. Oligo-recurrence was defined as < 3 lesions on choline-PET/CT only [1081] or conventional imaging with MRI/CT and/or bone scan [1082]. The sample size was small with 62 and 54 patients, respectively, and a substantial proportion of them had nodal disease only [1081]. Androgen deprivation therapy-free survival was the primary endpoint in one study which was longer with MDT than with surveillance [1081]. The primary endpoint in the ORIOLE trial was progression after 6 months which was significantly lower with SBRT than with surveillance (19% vs. 61%, p = 0.005) [1082]. Currently there is no data to suggest an improvement in OS. Two comprehensive reviews highlighted MDT (SABR) as a promising therapeutic approach that must still be considered as experimental until the results of the ongoing RCT are available [1083, 1084]. 6.4.9

Guidelines for the first-line treatment of metastatic disease

Recommendations Offer immediate systemic treatment with androgen deprivation therapy (ADT) to palliate symptoms and reduce the risk for potentially serious sequelae of advanced disease (spinal cord compression, pathological fractures, ureteral obstruction) to M1 symptomatic patients. Offer luteinising hormone-releasing hormone (LHRH) antagonists, especially to patients with an impending spinal cord compression or bladder outlet obstruction. Offer surgery and/or local radiotherapy to any patient with M1 disease and evidence of impending complications such as spinal cord compression or pathological fracture. Offer immediate systemic treatment to M1 patients asymptomatic from their tumour. Discuss deferred ADT with well-informed M1 patients asymptomatic from their tumour since it lowers the treatment-related side effects, provided the patient is closely monitored. Offer short-term administration of an older generation androgen receptor (AR) antagonist to M1 patients starting LHRH agonist to reduce the risk of the ‘flare-up’ phenomenon. Do not offer AR antagonist monotherapy to patients with M1 disease. Discuss combination therapy including ADT plus systemic therapy with all M1 patients. Do not offer ADT monotherapy to patients whose first presentation is M1 disease if they have no contraindications for combination therapy and have a sufficient life expectancy to benefit from combination therapy and are willing to accept the increased risk of side effects. Offer ADT combined with chemotherapy (docetaxel) to patients whose first presentation is M1 disease and who are fit for docetaxel. Offer ADT combined with abiraterone acetate plus prednisone or apalutamide or enzalutamide to patients whose first presentation is M1 disease and who are fit enough for the regimen. Offer ADT combined with prostate radiotherapy (using the doses from the STAMPEDE study) to patients whose first presentation is M1 disease and who have low volume of disease by CHAARTED criteria. Do not offer ADT combined with any local treatment (radiotherapy/surgery) to patients with high volume (CHAARTED criteria) M1 disease outside of clinical trials (except for symptom control). Do not offer ADT combined with surgery to M1 patients outside of clinical trials. Only offer metastasis-directed therapy to M1 patients within a clinical trial setting or welldesigned prospective cohort study.

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Strength rating Strong

Weak Strong Weak Weak Weak Strong Strong Strong

Strong Strong

Strong

Strong

Strong Strong

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6.5

Treatment: Castration-resistant PCa (CRPC)

6.5.1 Definition of CRPC Castrate serum testosterone < 50 ng/dL or 1.7 nmol/L plus either: a. Biochemical progression: Three consecutive rises in PSA at least one week apart resulting in two 50% increases over the nadir, and a PSA > 2 ng/mL or b. Radiological progression: The appearance of new lesions: either two or more new bone lesions on bone scan or a soft tissue lesion using RECIST (Response Evaluation Criteria in Solid Tumours) [1085]. Symptomatic progression alone must be questioned and subject to further investigation. It is not sufficient to diagnose CRPC. 6.5.2 Management of mCRPC - general aspects Selection of treatment for mCRPC is multifactorial and in general dependent on: • previous treatment for mHSPC and for non-mHSPC; • previous treatment for mCRPC; • quality of response and pace of progression on previous treatment; • known cross resistance between androgen receptor targeted agents (ARTA); • co-medication and known drug interactions (see approved summary of product characteristics); • known genetic alterations; • known histological variants and DNA repair deficiency (consider platinum or targeted therapy like polyADP ribose); • local approval status of drugs and reimbursement situation; • available clinical trials; • The patient and his co-morbidities. 6.5.2.1 Molecular diagnostics All metastatic patients should be offered somatic genomic testing for homologous repair and MMR defects, preferably on metastatic carcinoma tissue but testing on primary tumour may also be performed. Alternatively, but still less common, genetic testing on circulating tumour DNA (ctDNA) is an option and has been used in some trials. One test, the FoundationOne® Liquid CDx has been FDA approved [1086]. Defective MMR assessment can be performed by immunohistochemistry for MMR proteins (MSH2, MSH6, MLH1 and PMS2) and/or by next-generation sequencing assays [1087]. Germline testing for BRCA1/2, ATM and MMR is recommended for high risk and particularly for metastatic PCa if clinically indicated. Molecular diagnostics should be performed by a certified (accredited) institution using a standard NGS (Next Generation Sequencing) multiplication procedure (minimum depth of coverage of 200 X). The genes and respective exons should be listed; not only DNA for mutations but RNA needs to be examined for fusions and protein expression to obtain all clinically relevant information. A critical asset is the decision support helping to rate the mutations according to their clinical relevance [1088, 1089]. Level 1 evidence for the use of PARP-inhibitors has been reported [1090-1092]. Microsatellite instability (MSI)-high (or mismatch repair deficiency [MMR]) is rare in PCa, but for those patients, pembrolizumab has been approved by the FDA and could be a valuable additional treatment option [1093, 1094]. Germline molecular testing is discussed in Section 5.1.3 - Genetic testing for inherited PCa. Recommendations for germline testing are provided in Section 5.1.4. 6.5.3 Treatment decisions and sequence of available options Approved agents for the treatment of mCRPC in Europe are docetaxel, abiraterone/prednisolone, enzalutamide, cabazitaxel, olaparib and radium-223. In general, sequencing of ARTA like abiraterone and enzalutamide is not recommended particularly if the time of response to ADT and to the first ARTA was short (< 12 months) and high-risk features of rapid progression are present [1095, 1096]. The use of chemotherapy with docetaxel and subsequent cabazitaxel in the treatment sequence is recommended and should be applied early enough when the patient is still fit for chemotherapy. This is supported by high level evidence [1095]. 6.5.4 Non-metastatic CRPC Frequent PSA testing in men treated with ADT has resulted in earlier detection of biochemical progression. Of these men approximately one-third will develop bone metastases detectable on bone scan within two years [1097]. In men with CRPC and no detectable clinical metastases using bone scan and CT-scan, baseline PSA level, PSA velocity and PSA-DT have been associated with time to first bone metastasis, bone metastasisfree survival and OS [1097, 1098]. These factors may be used when deciding which patients should be evaluated for metastatic disease. A consensus statement by the PCa Radiographic Assessments for Detection

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of Advanced Recurrence (RADAR) group suggested a bone scan and a CT scan when the PSA reached 2 ng/mL and if this was negative, it should be repeated when the PSA reached 5 ng/mL, and again after every doubling of the PSA based on PSA testing every three months in asymptomatic men [1099]. Symptomatic patients should undergo relevant investigation regardless of PSA level. With more sensitive imaging techniques like PSMA PET/CT or whole-body MRI, more patients are diagnosed with early mCRPC [1100]. It remains unclear if the use of PSMA PET/CT in this setting improves outcome. Three large phase III RCTs, PROSPER [1101], SPARTAN [1102] and ARAMIS [1103], evaluated metastasis-free survival as the primary endpoint in patients with nmCRPC (M0 CRPC) treated with enzalutamide (PROSPER) vs. placebo or apalutamide (SPARTAN) vs. placebo or darolutamide vs. placebo (ARAMIS), respectively. The M0 status was established by CT and bone scans. Only patients at high risk for the development of metastasis with a short PSA-DT of < 10 months were included. Patient characteristics in both trials revealed that about two-thirds of participants had a PSA-DT of < 6 months. All trials showed a significant metastasis-free survival benefit (PROSPER: median metastasis-free survival was 36.6 months in the enzalutamide group vs. 14.7 months in the placebo group [HR for metastasis or death: 0.29, 95% CI: 0.24–0.35, p < 0.001]; SPARTAN: median metastasis-free survival was 40.5 months in the apalutamide group vs. 16.2 months in the placebo group [HR for metastasis or death, 0.28, 95% CI: 0.23–0.35, p < 0.001]; ARAMIS: median metastasis-free survival was 40.4 months in the darolutamide group vs. 18.4 months in the placebo group (HR: 0.41, 95% CI: 0.34–0.50; 2-sided p < 0.0001]). All 3 trials showed a survival benefit after a follow-up of more than 30 months. In view of the long-term treatment with these AR targeting agents in asymptomatic patients, potential adverse events need to be taken into consideration and the patient informed accordingly. 6.5.5 Metastatic CRPC The remainder of this section focuses on the management of men with proven metastatic CRPC (mCRPC) on conventional imaging. 6.5.5.1 Conventional androgen deprivation in CRPC Eventually men with PCa will show evidence of disease progression despite castration. Two trials have shown only a marginal survival benefit for patients remaining on LHRH analogues during second- and thirdline therapies [1104, 1105]. However, in the absence of prospective data, the modest potential benefits of continuing castration outweigh the minimal risk of treatment. In addition, all subsequent treatments have been studied in men with ongoing androgen suppression, therefore, it should be continued in these patients. Table 6.5.1: Randomised phase III controlled trials - first-line treatment of mCRPC Author DOCETAXEL SWOG 99-16 2004 [1106]

TAX 327 2008 [1107, 1108]

ABIRATERONE COU-AA-302 2013 [1109-1111]

Intervention

Comparison

Selection criteria

mitoxantrone, every 3 weeks, 12 mg/m2 prednisone 5 mg BID docetaxel, every mitoxantrone, 3 weeks, 75 mg/m2 every 3 weeks, 12 mg/m2, prednisone 5 mg BID Prednisone 5 mg or BID docetaxel, weekly, 30 mg/m2 prednisone 5 mg BID

OS: 17.52 vs. 15.6 mo. (p = 0.02, HR: 0.80; 95% CI: 0.67-0.97) PFS: 6.3 vs. 3.2 mo. (p < 0.001) OS: 19.2 for 3 weekly vs. 17.8 mo. 4-weekly and 16.3 in the control group. (p = 0.004, HR: 0.79, 95% CI: 0.67-0.93)

docetaxel/EMP, every 3 weeks, 60 mg/m2, EMP 3 x 280 mg/day

abiraterone + prednisone

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placebo + prednisone

Main outcomes

- No previous docetaxel. - ECOG 0-1. - PSA or radiographic progression. - No or mild symptoms. - No visceral metastases.

OS: 34.7 vs. 30.3 mo. (HR: 0.81, p = 0.0033). FU: 49.2 mo. rPFS: 16.5 vs. 8.3 mo. (p < 0.0001)

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ENZALUTAMIDE PREVAIL 2014 [1112]

enzalutamide

SIPULEUCEL-T SIPULEUCEL-T 2010 [1113]

2006 [1114]

IPATASERTIB IPAtential150 2020 [1115]

- No previous docetaxel. - ECOG 0-1. - PSA or radiographic progression. - No or mild symptoms. - 10% had visceral mets.

OS: 32.4 vs. 30.2 mo. (p < 0.001). FU: 22 mo. (p < 0.001 HR: 0.71, 95% CI: 0.60-0.84) rPFS: 20.0 mo. vs. 5.4 mo. HR: 0.186 (95% CI: 0.15-0.23) p < 0.0001)

sipuleucel-T [1113] placebo [1113]

- Some with previous docetaxel. - ECOG 0-1. - Asymptomatic or minimally symptomatic.

sipuleucel-T [1114] placebo [1114]

- ECOG 0-1. - No visceral met. - No corticosteroids.

OS: 25.8 vs. 21.7 mo. (p = 0.03 HR: 0.78, 95% CI: 0.61-0.98). FU: 34.1 mo. PFS: 3.7 vs. 3.6 mo. (no difference) OS: 25.9 vs. 21.4 mo. (p = 0.1). FU: 36 mo. PFS: 11.7 vs. 10.0 wk.

ipatasertib (400 mg/d) + abiraterone (1000 mg/d) + prednisone (5 mg bid)

placebo

abiraterone + prednisolone plus ipatasertib or abiraterone + prednisolone + placebo.

Previously untreated for mCRPC, asymptomatic/ mildly symptomatic, PTEN loss by IHC.

rPFS in PTEN loss (IHC) population: 18.5 vs. 16.5 mo. (p = 0.0335, HR: 0.77 95% CI: 0.61-0.98)

BID = twice a day; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; EMP =  estramustine; FU = follow-up; HR = hazard ratio; mo = month; PFS = progression-free survival; (r)PFS =  (radiographic) progression-free survival; OS = overall survival; ICH = immunohistochemistry.

6.5.6 First-line treatment of metastatic CRPC 6.5.6.1 Abiraterone Abiraterone was evaluated in 1,088 chemo-naïve, asymptomatic or mildly symptomatic mCRPC patients in the phase III COU-AA-302 trial. Patients were randomised to abiraterone acetate or placebo, both combined with prednisone [1109]. Patients with visceral metastases were excluded. The main stratification factors were ECOG PS 0 or 1 and asymptomatic or mildly symptomatic disease. Overall survival and rPFS were the co-primary endpoints. After a median follow-up of 22.2 months there was significant improvement of rPFS (median 16.5 vs. 8.2 months, HR: 0.52, p < 0.001) and the trial was unblinded. At the final analysis with a median follow-up of 49.2 months, the OS endpoint was significantly positive (34.7 vs. 30.3 months, HR: 0.81, 95% CI: 0.70–0.93, p = 0.0033) [1111]. Adverse events related to mineralocorticoid excess and liver function abnormalities were more frequent with abiraterone, but mostly grade 1–2. Sub-set analysis of this trial showed the drug to be equally effective in an elderly population (> 75 years) [1116]. 6.5.6.2 Enzalutamide A randomised phase III trial (PREVAIL) included a similar patient population and compared enzalutamide and placebo [1112]. Men with visceral metastases were eligible but the numbers included were small. Corticosteroids were allowed but not mandatory. PREVAIL was conducted in a chemo-naïve mCRPC population of 1,717 men and showed a significant improvement in both co-primary endpoints, rPFS (HR: 0.186, CI: 0.15–0.23, p < 0.0001), and OS (HR: 0.706, CI: 0.6–0.84, p < 0.001). A > 50% decrease in PSA was seen in 78% of patients. The most common clinically relevant adverse events were fatigue and hypertension. Enzalutamide was equally effective and well tolerated in men > 75 years [1117] as well as in those with or without visceral metastases [1118]. However, for men with liver metastases, there seems to be no discernible benefit [1118, 1119]. Enzalutamide has also been compared with bicalutamide 50 mg/day in a randomised double blind phase II study (TERRAIN) [1120] showing a significant improvement in PFS (15.7 months vs. 5.8 months, HR: 0.44, p < 0.0001) in favour of enzalutamide. With extended follow-up and final analysis the benefit in OS and rPFS were confirmed [1121].

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6.5.6.3 Docetaxel A statistically significant improvement in median survival of 2.0–2.9 months has been shown with docetaxelbased chemotherapy compared to mitoxantrone plus prednisone [1108, 1122]. The standard first-line chemotherapy is docetaxel 75 mg/m2, 3-weekly doses combined with prednisone 5 mg twice a day (BID), up to 10 cycles. Prednisone can be omitted if there are contraindications or no major symptoms. The following independent prognostic factors; visceral metastases, pain, anaemia (Hb < 13 g/dL), bone scan progression, and prior estramustine may help stratify the response to docetaxel. Patients can be categorised into three risk groups: low risk (0 or 1 factor), intermediate (2 factors) and high risk (3 or 4 factors), and show three significantly different median OS estimates of 25.7, 18.7 and 12.8 months, respectively [1123]. Age by itself is not a contraindication to docetaxel [1124] but attention must be paid to careful monitoring and co-morbidities as discussed in Section 5.4 - Estimating life expectancy and health status [1125]. In men with mCRPC who are thought to be unable to tolerate the standard dose and schedule, docetaxel 50 mg/m2 every two weeks seems to be well tolerated with less grade 3–4 adverse events and a prolonged time to treatment failure [1126]. 6.5.6.4 Sipuleucel-T In 2010 a phase III trial of sipuleucel-T showed a survival benefit in 512 asymptomatic or minimally symptomatic mCRPC patients [1113]. After a median follow-up of 34 months, the median survival was 25.8 months in the sipuleucel-T group compared to 21.7 months in the placebo group, with a HR of 0.78 (p = 0.03). No PSA decline was observed and PFS was similar in both arms. The overall tolerance was very good, with more cytokine-related adverse events grade 1–2 in the sipuleucel-T group, but the same grade 3–4 adverse events in both arms. Sipuleucel-T is not available in Europe (and has had its licence withdrawn). 6.5.6.5 Ipatasertib The AKT inhibitor ipatasertib in combination with abiraterone plus prednisone was studied in asymptomatic or mildly symptomatic patients with PTEN loss by IHC and previously untreated for mCRPC. The randomised phase III trial (IPAtential) showed a significant benefit for the first endpoint rPFS in the PTEN loss (IHC) population (18.5 vs. 16.5 mo; p = 0,0335, HR: 0.77, 95% CI: 0.61–0,98). The OS results are still pending. Side effects of the AKT inhibitor ipatasertib include rash and diarrhoea [750]. This combination is still investigational [1115]. Table 6.5.2: Randomised controlled phase III - second-line/third-line trials in mCRPC Author Intervention ABIRATERONE COU-AA-301 abiraterone + 2012 [1127] prednisone HR

Comparison

Selection criteria

Main outcomes

placebo + prednisone

Previous docetaxel. ECOG 0-2. PSA or radiographic progression.

OS: 15.8 vs. 11.2 mo. (p < 0.0001, HR: 0.74, 95% CI: 0.64-0.86; p  ARTA followed by PARP inhibitor Both olaparib and rucaparib are active in biomarker-selected mCRPC patients after ARTA and docetaxel in either sequence [1092, 1149]. 6.5.8.2.5 ARTA before or after docetaxel There is level 1 evidence for both sequences (see Table 6.5.2). 6.5.8.2.6 ARTA –> docetaxel -> cabazitaxel or docetaxel –> ARTA -> cabazitaxel Both third-line treatment sequences are supported by level 1 evidence. Of note, there is high level evidence favouring cabazitaxel vs. a second ARTA after docetaxel and one ARTA. CARD is the first prospective randomised phase III trial adressing this question (see Table 6.5.2) [1095]. 6.5.9 Prostate-specific membrane antigen (PSMA) therapy 6.5.9.1 Background During the 90s several radiopharmaceuticals including phosphorous-32, strontium-89, yttrium-90, samarium-153, and rhenium-186 [1162] were developed for the treatment of bone pain secondary to metastasis from PCa. They were effective at palliation; relieving pain and improving QoL, especially in the setting of diffuse bone metastasis. However, they never gained widespread adoption. The first radioisotope to demonstrate a survival benefit was radium-223 (see Section 6.5.7.4). 6.5.9.2 PSMA-based therapy The increasing use of PSMA PET as a diagnostic tracer and the realisation that this allowed identification of a greater number of metastatic deposits led to attempts to treat cancer by replacing the imaging isotope with a therapeutic isotope which accumulates where the tumour is demonstrated (theranostics) [1164]. Therefore, after identification of the target usually with diagnostic 68Gallium-labelled PSMA, therapeutic radiopharmaceuticals labelled with beta (lutetium-177 or ytrium-90) or a (actinium-225) emitting isotopes could be used to treat metastatic PCa. At present, all of these agents should be regarded as investigational. The PSMA therapeutic radiopharmaceutical supported with the most robust data is 177Lu-PSMA-617. The first patient was treated in 2014 and early clinical studies evaluating the safety and efficacy of Lu-PSMA therapy have demonstrated promising results, despite the fact that a significant proportion of men had already progressed on multiple therapies [1165]. Nonetheless, most of the literature is based on single-centre experience and RCTs are lacking [1166]. Recently, data from uncontrolled prospective phase II trials have been published reporting high response rates with low toxic effects [1167, 1168]. Positive signals are coming from a randomised phase II trial comparing Lu-PSMA with cabazitaxel in ARTA and docetaxel pre-treated patients. The primary endpoint of PSA reduction > 50% was achieved in highly selected patients (PSMA- and FDG PET/ CT criteria) was superior with Lu-PSMA [1169]. More robust data are expected from ongoing trials. 6.5.10 Immunotherapy for mCRPC The immune checkpoint inhibitor pembrolizumab was approved by the FDA for all MMR–deficient cancers or in those with instable microsatellite status (MSI-high) [1093]. This also applies to PCa but is a very rare finding in this tumour entity [1094]. In all other PCa patients pembrolizumab monotherapy is still experimental. It shows limited anti-tumour activity with an acceptable safety profile, again in a small subset of patients. A phase II trial enrolled 258 patients treated with pembrolizumab [1163]. The objective response rate was around 4%, but those responses were durable. Combination immunotherapy is under investigation. 6.5.11 Monitoring of treatment Baseline examinations should include a medical history, clinical examination as well as baseline blood tests (PSA, total testosterone level, full blood count, renal function, baseline liver function tests, alkaline phosphatase), bone scan and CT of chest, abdomen and pelvis [1170, 1171]. The use of choline or PSMA

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PET/CT scans for progressing CRPC is unclear and most likely not as beneficial as for patients with BCR or hormone-naïve disease. Flares, PSMA upregulation and discordant results compared with PSA response or progression on ARTA have been described [1172]. Prostate-specific antigen alone is not reliable enough [1173] for monitoring disease activity in advanced CRPC since visceral metastases may develop in men without rising PSA [1174]. Instead, the PCWG2 recommends a combination of bone scintigraphy and CT scans, PSA measurements and clinical benefit in assessing men with CRPC [1122]. A majority of experts at the 2015 Advanced Prostate Cancer Consensus Conference (APCCC) suggested regular review and repeating blood profile every two to three months with bone scintigraphy and CT scans at least every six months, even in the absence of a clinical indication [1170]. This reflects that the agents with a proven OS benefit all have potential toxicity and considerable cost and patients with no objective benefit should have their treatment modified. The APCCC participants stressed that such treatments should not be stopped for PSA progression alone. Instead, at least two of the three criteria (PSA progression, radiographic progression and clinical deterioration) should be fulfilled to stop treatment. For trial purposes, the updated PCWG3 put more weight on the importance of documenting progression in existing lesions and introduced the concept of no longer ‘clinically benefiting‘ to underscore the distinction between first evidence of progression and the clinical need to terminate or change treatment [1175]. These recommendations also seem valid for clinical practice outside trials. 6.5.12 When to change treatment The timing of mCRPC treatment change remains a matter of debate in mCRPC although it is clearly advisable to start or change treatment immediately in men with symptomatic progressing metastatic disease. Preferably, any treatment change should precede development of de novo symptoms or worsening of existing symptoms. Although, the number of effective treatments is increasing, head-to-head comparisons are still rare, as are prospective data assessing the sequencing of available agents. Therefore it is not clear how to select the most appropriate ‘second-line‘ treatment, in particular in patients without HRR alterations or other biomarkers. A positive example, however, is the CARD trial which clearly established cabazitaxel as the better third-line treatment in docetaxel pre-treated patients after one ARTA compared to the use of a second ARTA [1095]. The ECOG PS has been used to stratify patients. Generally men with a PS of 0–1 are likely to tolerate treatments and those with a PS of > 2 are less likely to benefit. However, it is important that treatment decisions are individualised, in particular when symptoms related to disease progression are impacting on PS. In such cases, a trial of active life-prolonging agents to establish if a given treatment will improve the PS may be appropriate. Sequencing of treatment is discussed in a summery paper published following the St. Gallen Advanced Prostate Cancer Consensus Conference 2019 [1176]. 6.5.13 Symptomatic management in metastatic CRPC Castration-resistant PCa is usually a debilitating disease often affecting the elderly male. A multidisciplinary approach is required with input from urologists, medical oncologists, radiation oncologists, nurses, psychologists and social workers [1176, 1177]. Critical issues of palliation must be addressed when considering additional systemic treatment, including management of pain, constipation, anorexia, nausea, fatigue and depression. 6.5.13.1 Common complications due to bone metastases Most patients with CRPC have painful bone metastases. External beam radiotherapy is highly effective, even as a single fraction [1178, 1179]. A single infusion of a third generation bisphosphonate could be considered when RT is not available [1180]. Common complications due to bone metastases include vertebral collapse or deformity, pathological fractures and spinal cord compression. Cementation can be an effective treatment for painful spinal fracture whatever its origin, clearly improving both pain and QoL [1181]. It is important to offer standard palliative surgery, which can be effective for managing osteoblastic metastases [1182, 1183]. Impending spinal cord compression is an emergency. It must be recognised early and patients should be educated to recognise the warning signs. Once suspected, high-dose corticosteroids must be given and MRI performed as soon as possible. A systematic neurosurgery or orthopaedic surgeon consultation should be planned to discuss a possible decompression, followed by EBRT [1184]. Otherwise, EBRT with, or without, systemic therapy, is the treatment of choice. 6.5.13.2 Preventing skeletal-related events 6.5.13.2.1 Bisphosphonates Zoledronic acid has been evaluated in mCRPC to reduce skeletal-related events (SRE). This study was conducted when no active anti-cancer treatments, but for docetaxel, were available. Six hundred and forty three patients who had CRPC with bone metastases were randomised to receive zoledronic acid, 4 or 8 mg every three weeks for 15 consecutive months, or placebo [1185]. The 8 mg dose was poorly tolerated and reduced to 4 mg but did not show a significant benefit. However, at 15 and 24 months of follow-up, patients

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treated with 4 mg zoledronic acid had fewer SREs compared to the placebo group (44 vs. 33%, p = 0.021) and in particular fewer pathological fractures (13.1 vs. 22.1%, p = 0.015). Furthermore, the time to first SRE was longer in the zoledronic acid group. No survival benefit has been seen in any prospective trial with bisphosphonates. 6.5.13.2.2 RANK ligand inhibitors Denosumab is a fully human monoclonal antibody directed against RANKL (receptor activator of nuclear factor kappa-B ligand), a key mediator of osteoclast formation, function, and survival. In M0 CRPC, denosumab has been associated with increased bone-metastasis-free survival compared to placebo (median benefit: 4.2 months, HR: 0.85, p = 0.028) [1178]. This benefit did not translate into a survival difference (43.9 compared to 44.8 months, respectively) and neither the FDA or the EMA have approved denosumab for this indication [1186]. The efficacy and safety of denosumab (n = 950) compared with zoledronic acid (n = 951) in patients with mCRPC was assessed in a phase III trial. Denosumab was superior to zoledronic acid in delaying or preventing SREs as shown by time to first on-study SRE (pathological fracture, radiation or surgery to bone, or spinal cord compression) of 20.7 vs. 17.1 months, respectively (HR: 0.82, p = 0.008). Both urinary N-telopeptide and bone-specific alkaline phosphatase were significantly suppressed in the denosumab arm compared with the zoledronic acid arm (p < 0.0001 for both). However, these findings were not associated with any survival benefit and in a recent post-hoc re-evaluation of endpoints, denosumab showed identical results when comparing SREs and symptomatic skeletal events [1187]. The potential toxicity (e.g., osteonecrosis of the jaw, hypocalcaemia) of these drugs must always be kept in mind (5–8.2% in M0 CRPC and mCRPC, respectively) [1187-1189]. Patients should have a dental examination before starting therapy as the risk of jaw necrosis is increased by several risk factors including a history of trauma, dental surgery or dental infection [1190]. Also, the risk for osteonecrosis of the jaw increased numerically with the duration of use in a pivotal trial [1191] (one year vs. two years with denosumab), but this was not statistically significant when compared to zoledronic acid [1186]. According to the EMA, hypocalcaemia is a concern in patients treated with denosumab and zoledronic acid. Hypocalcaemia must be corrected by adequate intake of calcium and vitamin D before initiating therapy [1192]. Hypocalcaemia should be identified and prevented during treatment with bone protective agents (risk of severe hypocalcaemia is 8% and 5% for denosumab and zoledronic acid, respectively) [1189]. Serum calcium should be measured in patients starting therapy and monitored during treatment, especially during the first weeks and in patients with risk factors for hypocalcaemia or on other medication affecting serum calcium. Daily calcium (> 500 mg) and vitamin D (> 400 IU equivalent) are recommended in all patients, unless in case of hypercalcaemia [1189, 1193, 1194]. 6.5.14

Summary of evidence and guidelines for life-prolonging treatments of castrate-resistant disease

Summary of evidence First-line treatment for mCRPC will be influenced by which treatments were used when metastatic cancer was first discovered. No clear-cut recommendation can be made for the most effective drug for first-line CRPC treatment (i.e., hormone therapy, chemotherapy or radium-223) as no validated predictive factors exist.

Recommendations Ensure that testosterone levels are confirmed to be < 50 ng/dL before diagnosing castrateresistant PCa (CRPC). Counsel, manage and treat patients with metastatic CRPC (mCRPC) in a multidisciplinary team. Treat patients with mCRPC with life-prolonging agents. Offer mCRPC patients somatic and/or germline molecular testing as well as testing for mismatch repair deficiencies or microsatellite instability.

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6.5.15

Guidelines for systematic treatments of castrate-resistant disease

Recommendations Base the choice of treatment on the performance status, symptoms, co-morbidities, location and extent of disease, genomic profile, patient preference, and on the previous treatment for hormone-sensitive metastatic PCa (mHSPC) (alphabetical order: abiraterone, cabazitaxel, docetaxel, enzalutamide, olaparib, radium-223, sipuleucel-T). Offer patients with mCRPC who are candidates for cytotoxic therapy and are chemotherapy naïve docetaxel with 75 mg/m2 every 3 weeks. Offer patients with mCRPC and progression following docetaxel chemotherapy further life-prolonging treatment options, which include abiraterone, cabazitaxel, enzalutamide, radium-223 and olaparib in case of DNA homologous recombination repair (HRR) alterations. Base further treatment decisions of mCRPC on performance status, previous treatments, symptoms, co-morbidities, genomic profile, extent of disease and patient preference. Offer abiraterone or enzalutamide to patients previously treated with one or two lines of chemotherapy. Avoid sequencing of androgen receptor targeted agents. Offer chemotherapy to patients previously treated with abiraterone or enzalutamide. Offer cabazitaxel to patients previously treated with docetaxel. Offer cabazitaxel to patients previously treated with docetaxel and progressing within 12 months of treatment with abiraterone or enzalutamide. Novel agents Offer poly(ADP-ribose) polymerase (PARP) inhibitors to pre-treated mCRPC patients with relevant DNA repair gene mutations.

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6.5.16 Guidelines for supportive care of castrate-resistant disease These recommendations are in addition to appropriate systemic therapy. Recommendations Offer bone protective agents to patients with mCRPC and skeletal metastases to prevent osseous complications. Monitor serum calcium and offer calcium and vitamin D supplementation when prescribing either denosumab or bisphosphonates. Treat painful bone metastases early on with palliative measures such as intensity-modulated radiation therapy plus image-guided radiation therapy and adequate use of analgesics. In patients with spinal cord compression start immediate high-dose corticosteroids and assess for spinal surgery followed by irradiation. Offer radiation therapy alone if surgery is not appropriate. 6.5.17

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Recommendation Offer apalutamide, darolutamide or enzalutamide to patients with M0 CRPC and a high risk of developing metastasis (PSA-DT < 10 months) to prolong time to metastases and overall survival.

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Summary of guidelines for the treatment of prostate cancer

Table 6.6.1: EAU risk groups for biochemical recurrence of localised and locally-advanced prostate Definition Low-risk PSA < 10 ng/mL and GS < 7 (ISUP grade 1) and cT1-2a Localised

Intermediate-risk High-risk any PSA PSA > 20 ng/mL PSA 10-20 ng/mL or GS 7 (ISUP grade 2/3) or GS > 7 (ISUP grade 4/5) any GS (any ISUP grade) cT3-4 or cN+ or cT2c or cT2b Locally advanced

GS = Gleason score; ISUP = International Society for Urological Pathology; PSA = prostate-specific antigen.

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6.6.1

General guidelines recommendations for treatment of prostate cancer

Recommendations Inform patients that based on robust current data with up to 12 years of follow-up, no active treatment modality has shown superiority over any other active management options or deferred active treatment in terms of overall- and PCa-specific survival for clinically localised disease. Offer a watchful waiting policy to asymptomatic patients with a life expectancy < 10 years (based on co-morbidities). Inform patients that all active treatments have side effects. Surgical treatment Inform patients that no surgical approach (open-, laparoscopic- or robotic radical prostatectomy) has clearly shown superiority in terms of functional or oncological results. When a lymph node dissection (LND) is deemed necessary, perform an extended LND template for optimal staging. Do not perform nerve-sparing surgery when there is a risk of ipsilateral extracapsular extension (based on cT stage, ISUP grade, nomogram, multiparametric magnetic resonance imaging). Do not offer neoadjuvant androgen deprivation therapy before surgery. Radiotherapeutic treatment Offer intensity-modulated radiation therapy (IMRT) plus image-guided radiation therapy (IGRT) for definitive treatment of PCa by external-beam radiation therapy. Offer moderate hypofractionation (HFX) with IMRT including IGRT to the prostate, to patients with localised disease. Ensure that moderate HFX adheres to radiotherapy protocols from trials with equivalent outcome and toxicity, i.e. 60 Gy/20 fractions in 4 weeks or 70 Gy/28 fractions in 6 weeks. Offer low-dose rate (LDR) brachytherapy monotherapy to patients with good urinary function and low- or good prognosis intermediate-risk localised disease. Offer LDR or high-dose rate brachytherapy boost combined with IMRT including IGRT to patients with good urinary function and intermediate-risk disease with adverse features or high-risk disease. Active therapeutic options outside surgery and radiotherapy Only offer cryotherapy and high-intensity focused ultrasound within a clinical trial setting or well-designed prospective cohort study. Only offer focal therapy within a clinical trial setting or well-designed prospective cohort study. 6.6.2

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Guidelines recommendations for the various disease stages

Recommendations Low-risk disease Active Selection of patients surveillance (AS) Offer AS to patients with life expectancy > 10 years and low-risk disease. If a patient has had upfront multiparametric magnetic resonance imaging (mpMRI) followed by systematic and targeted biopsies there is no need for confirmatory biopsies. Patients with intraductal and cribiform histology on biopsy should be excluded from AS. Perform a mpMRI before a confirmatory biopsy if no mpMRI has been performed before the initial biopsy. Take both targeted biopsy (of any PI-RADS > 3 lesion) and systematic biopsy if a confirmatory biopsy is performed. Follow-up strategy Perform serum prostate-specific antigen (PSA) assessment every 6 months. Perform digital rectal examination (DRE) every 12 months. Counsel patients about the possibility of needing further treatment in the future.

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Active treatment

Offer surgery and radiotherapy (RT) as alternatives to AS to patients suitable for such treatments and who accept a trade-off between toxicity and prevention of disease progression. Pelvic lymph node Do not perform a PLND (estimated risk for pN+ < 5%). dissection (PLND) Radiotherapeutic Offer low-dose rate (LDR) brachytherapy to patients with low-risk PCa, treatment without a recent transurethral resection of the prostate (TURP) and with a good International Prostatic Symptom Score (IPSS). Use intensity-modulated radiation therapy (IMRT) plus image-guided radiation therapy (IGRT) with a total dose of 74-80 Gy or moderate hypofractionation (60 Gy/20 fx in 4 weeks, or 70 Gy/28 fx in 6 weeks), without androgen deprivation therapy (ADT). Other therapeutic Do not offer ADT monotherapy to asymptomatic men not able to options receive any local treatment. Only offer whole gland treatment (such as cryotherapy, high-intensity focused ultrasound [HIFU], etc.) or focal treatment within a clinical trial setting or well-designed prospective cohort study. Intermediate-risk disease Active surveillance Offer AS to highly selected patients with ISUP grade group 2 disease (i.e. < 10% pattern 4, PSA < 10 ng/mL, < cT2a, low disease extent on imaging and biopsy) accepting the potential increased risk of metastatic progression. Radical Offer RP to patients with intermediate-risk disease and a life Prostatectomy expectancy > 10 years. (RP) Offer nerve-sparing surgery to patients with a low risk of extracapsular disease. Extended pelvic Perform an ePLND in intermediate-risk disease if the estimated risk for lymph node positive lymph nodes exceeds 5%. dissection (ePLND) Radiotherapeutic Offer LDR brachytherapy to intermediate-risk patients with ISUP grade treatment 2 with < 33% of biopsy cores involved, without a recent TURP and with a good IPSS Score. For IMRT plus IGRT, use a total dose of 76-78 Gy or moderate hypofractionation (60 Gy/20 fx in 4 weeks or 70 Gy/28 fx in 6 weeks), in combination with short-term ADT (4 to 6 months). In patients not willing to undergo ADT, use a total dose of IMRT plus IGRT (76-78 Gy) or moderate hypofractionation (60 Gy/20 fx in 4 weeks or 70 Gy/28 fx in 6 weeks) or a combination with brachytherapy. Other therapeutic Only offer whole-gland ablative therapy (such as cryotherapy, HIFU, options etc.) or focal ablative therapy for intermediate-risk disease within a clinical trial setting or well-designed prospective cohort study. Do not offer ADT monotherapy to intermediate-risk asymptomatic men not able to receive any local treatment. High-risk localised disease Radical Offer RP to selected patients with high-risk localised PCa, as part of prostatectomy potential multi-modal therapy. Extended pelvic Perform an ePLND in high-risk PCa. lymph node Do not perform a frozen section of nodes during RP to decide whether dissection to proceed with, or abandon, the procedure. Radiotherapeutic In patients with high-risk localised disease, use IMRT plus IGRT with treatments 76-78 Gy in combination with long-term ADT (2 to 3 years). In patients with high-risk localised disease, use IMRT and IGRT with brachytherapy boost (either HDR or LDR), in combination with longterm ADT (2 to 3 years). Therapeutic Do not offer either whole gland nor focal therapy to patients with highoptions outside risk localised disease. surgery and Only offer ADT monotherapy to those patients unwilling or unable to radiotherapy receive any form of local treatment if they have a PSA-doubling time < 12 months, and either a PSA > 50 ng/mL or a poorly-differentiated tumour. 120

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Locally-advanced disease Radical Offer RP to selected patients with locally-advanced PCa as part of prostatectomy multi-modal therapy. Extended pelvic Perform an ePLND prior to RP in locally-advanced PCa. lymph node dissection Radiotherapeutic In patients with locally-advanced disease, offer IMRT plus IGRT in treatments combination with long-term ADT. Offer long-term ADT for at least two years. Therapeutic Do not offer whole gland treatment or focal treatment to patients with options outside locally-advanced PCa. surgery and Only offer ADT monotherapy to those patients unwilling or unable to radiotherapy receive any form of local treatment if they have a PSA-doubling time < 12 months, and either a PSA > 50 ng/mL, a poorly-differentiated tumour or troublesome local disease-related symptoms. Offer patients with cN1 disease a local treatment (either RP or IMRT plus IGRT) plus long-term ADT. Adjuvant treatment after radical prostatectomy pN0 & pN1 Do not prescribe adjuvant ADT in pN0 patients. disease Only offer adjuvant intensity-modulated radiation therapy (IMRT) plus image-guided radiation therapy (IGRT) to high-risk patients (pN0) with at least two out of three high-risk features (ISUP grade group 4–5, pT3 ± positive margins). Discuss three management options with patients with pN1 disease after an ePLND, based on nodal involvement characteristics: 1. Offer adjuvant ADT; 2. Offer adjuvant ADT with additional IMRT plus IGRT; 3. Offer observation (expectant management) to a patient after eLND and 0.2 ng/mL if the results will influence subsequent treatment decisions Treat men with no evidence of metastatic disease with salvage RT and additional hormonal therapy.

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6.6.3

Guidelines for metastatic disease, second-line and palliative treatments

Recommendations Metastatic disease in a first-line setting M1 patients Offer immediate systemic treatment with ADT to palliate symptoms and reduce the risk for potentially serious sequelae of advanced disease (spinal cord compression, pathological fractures, ureteral obstruction) to M1 symptomatic patients. Offer luteinising hormone-releasing hormone (LHRH) antagonists, especially to patients with an impending spinal cord compression or bladder outlet obstruction. Offer surgery and/or local radiotherapy to any patient with M1 disease and evidence of impending complications such as spinal cord compression or pathological fracture. Offer immediate systemic treatment to M1 patients asymptomatic from their tumour. Discuss deferred ADT with well-informed M1 patients asymptomatic from their tumour since it lowers the treatment-related side effects, provided the patient is closely monitored. Offer short-term administration of an older generation androgen receptor (AR) antagonist to M1 patients starting LHRH agonist to reduce the risk of the ‘flare-up’ phenomenon. Do not offer AR antagonists monotherapy to patients with M1 disease. Discuss combination therapy including ADT plus systemic therapy with all M1 patients. Do not offer ADT monotherapy to patients whose first presentation is M1 disease if they have no contraindications for combination therapy and have a sufficient life expectancy to benefit from combination therapy and are willing to accept the increased risk of side effects. Offer ADT combined with chemotherapy (docetaxel) to patients whose first presentation is M1 disease and who are fit for docetaxel. Offer ADT combined with abiraterone acetate plus prednisone or apalutamide or enzalutamide to patients whose first presentation is M1 disease and who are fit for the regimen. Offer ADT combined with prostate radiotherapy (using the doses from the STAMPEDE study) to patients whose first presentation is M1 disease and who have low volume of disease by CHAARTED criteria. Do not offer ADT combined with any local treatment (radiotherapy/ surgery) to patients with high-volume M1 disease (CHAARTED criteria) outside of clinical trials (except for symptom control). Do not offer ADT combined with surgery to M1 patients outside of clinical trials. Only offer metastasis-directed therapy to M1 patients within a clinical trial setting or well-designed prospective cohort study. Biochemical recurrence after treatment with curative intent Biochemical Offer monitoring, including PSA, to EAU Low-Risk BCR patients. recurrence Offer early salvage IMRT plus IGRT to men with two consecutive PSA after radical rises. prostatectomy A negative PET/CT scan should not delay salvage radiotherapy (SRT), (RP) if otherwise indicated. Do not wait for a PSA threshold before starting treatment. Once the decision for SRT has been made, SRT (at least 66 Gy) should be given as soon as possible. Offer hormonal therapy in addition to SRT to men with biochemical recurrence (BCR).

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Biochemical recurrence after RT

Offer monitoring, including PSA, to EAU Low-Risk BCR patients. Only offer salvage RP, brachytherapy, HIFU, or cryosurgical ablation to highly selected patients with biopsy proven local recurrence within a clinical trial setting or well-designed prospective cohort study undertaken in experienced centres. Do not offer ADT to M0 patients with a PSA-DT > 12 months.

Systemic salvage treatment Life-prolonging treatments of castration-resistant disease Ensure that testosterone levels are confirmed to be < 50 ng/dL, before diagnosing castration-resistant PCa (CRPC). Counsel, manage and treat patients with metastatic CRPC (mCRPC) in a multidisciplinary team. Treat patients with mCRPC with life-prolonging agents. Offer mCRPC patients somatic and/or germline molecular testing as well as testing for mismatch repair deficiencies or microsatellite instability. Systemic treatments of castrate-resistant disease Base the choice of treatment on the performance status (PS), symptoms, co-morbidities, location and extent of disease, genomic profile, patient preference, and on the previous treatment for hormonesensitive metastatic PCa (mHSPC) (alphabetical order: abiraterone, cabazitaxel, docetaxel, enzalutamide, olaparib, radium-223, sipuleucel-T). Offer patients with mCRPC who are candidates for cytotoxic therapy and are chemotherapy naïve docetaxel with 75 mg/m2 every 3 weeks. Offer patients with mCRPC and progression following docetaxel chemotherapy further life-prolonging treatment options, which include abiraterone, cabazitaxel, enzalutamide, radium-223 and olaparib in case of DNA homologous recombination repair (HRR). Base further treatment decisions of mCRPC on pre-treatment PS status, previous treatments, symptoms, co-morbidities, genomic profile, extent of disease and patient preference. Offer abiraterone or enzalutamide to patients previously treated with one or two lines of chemotherapy. Avoid sequencing of androgen receptor targeted agents. Offer chemotherapy to patients previously treated with abiraterone or enzalutamide. Offer cabazitaxel to patients previously treated with docetaxel. Offer cabazitaxel to patients previously treated with docetaxel and progressing within 12 months of treatment with abiraterone or enzalutamide. Novel agents Offer poly(ADP-ribose) polymerase (PARP) inhibitors to pre-treated mCRPC patients with relevant DNA repair gene mutations. Supportive care of castration-resistant disease Offer bone protective agents to patients with mCRPC and skeletal metastases to prevent osseous complications. Monitor serum calcium and offer calcium and vitamin D supplementation when prescribing either denosumab or bisphosphonates. Treat painful bone metastases early on with palliative measures such as IMRT plus IGRT and adequate use of analgesics. In patients with spinal cord compression start immediate high-dose corticosteroids and assess for spinal surgery followed by irradiation. Offer radiation therapy alone if surgery is not appropriate. Non-metastatic castrate-resistant disease Offer apalutamide, darolutamide or enzalutamide to patients with M0 CRPC and a high risk of developing metastasis (PSA-DT < 10 months) to prolong time to metastases and overall survival.

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7.

FOLLOW-UP

The rationale for following up patients is to assess immediate- and long-term oncological results, ensure treatment compliance and allow initiation of further therapy, when appropriate. In addition, follow-up allows monitoring of side effects or complications of therapy, functional outcomes and an opportunity to provide psychological support to PCa survivors, all of which is covered in Chapter 8.

7.1

Follow-up: After local treatment

7.1.1 Definition Local treatment is defined as RP or RT, either by IMRT plus IGRT or LDR- or HDR-brachytherapy, or any combination of these, including neoadjuvant and adjuvant therapy. Unestablished alternative treatments such as HIFU, cryosurgery and focal therapy options do not have a well-defined, validated, PSA cut-off to define BCR but follow the general principles as presented in this section. In general, a confirmed rising PSA is considered a sign of disease recurrence. 7.1.2 Why follow-up? The first post-treatment clinic visit focuses on detecting treatment-related complications and assist patients in coping with their new situation apart from providing information on the pathological analysis. Men with PCa are at increased risk of depression and attention for mental health status is required [1195, 1196]. Tumour or patient characteristics may prompt changing the follow-up schedule. 7.1.3 How to follow-up? The procedures indicated at follow-up visits vary according to the clinical situation. A disease-specific history is mandatory at every follow-up visit and includes psychological aspects, signs of disease progression, and treatment-related complications. Evaluation of treatment-related complications in the post-treatment period is highlighted in Sections 6.1.2.4, 6.1.2.4.3, 6.3.9.2, 6.3.10.2.2, 6.3.11.2 and 8.2. The examinations used for cancer-related follow-up after curative surgery or RT are discussed below. 7.1.3.1 Prostate-specific antigen monitoring Measurement of PSA is the cornerstone of follow-up after local treatment. While PSA thresholds depend on the local treatment used, PSA recurrence almost always precedes clinical recurrence [914, 1197]. The key question is to establish when a PSA rise is clinically significant since not all PSA increases have the same clinical value (see Section 6.3) [916]. 7.1.3.1.1 Active surveillance follow-up Patients included in an AS programme should be monitored according to the recommendations presented in Section 6.2.2. 7.1.3.1.2 Prostate-specific antigen monitoring after radical prostatectomy Following RP, the PSA level is expected to be undetectable (< 0.1 ng/mL). Prostate-specific antigen is generally determined every 3 months in the first year, every 6 months until 3 years and yearly thereafter but evidence for a specific interval is low [467] and mainly based on the observation that early recurrences are more likely to be associated with more rapid progression [916, 1198, 1199]. Prostate-specific antigen level is expected to be undetectable 2 months after a successful RP [1200]. As mentioned in Section 6.3.2 the PSA-threshold at relapse best predicting metastases after RP is > 0.4 ng/mL. Persistently measurable PSA in patients treated with RP is discussed in Section 6.2.6 - Persistent PSA. Ultrasensitive PSA assays remain controversial for routine follow-up after RP. Men with an ultrasensitive PSA nadir < 0.01 ng/mL have a high (96%) likelihood of remaining relapse free within 2 years [1201]. In addition, post-RP ultrasensitive PSA levels > 0.01 ng/mL in combination with clinical characteristics such as ISUP grade and surgical margin status may predict PSA progression and can be useful to establish follow-up intervals [1199]. Lastly, PSA and associated PSA-DT [1202] calculated prior to 0.2 ng/mL may help identify suitable candidates for early intervention [1203]. Prostate-specific antigen monitoring after salvage RT to the prostatic fossa is done at similar intervals and an early PSA rise predicts more rapid progression [1198]. 7.1.3.1.3 Prostate-specific antigen monitoring after radiotherapy Following RT, PSA drops more slowly as compared to post RP. A nadir < 0.5 ng/mL is associated with a favourable outcome after RT although the optimal cut-off value remains controversial [1204]. The interval before reaching the nadir can be up to 3 years, or more. At the 2006 RTOG-ASTRO Consensus Conference the Phoenix definition of radiation failure was proposed to establish a better correlation between definition

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and clinical outcome (mainly metastases), namely, an increase of 2 ng/mL above the post-treatment PSA nadir [915]. This definition also applies to patients who received HT [915]. 7.1.3.1.4 Digital rectal examination Local recurrence after curative treatment is possible without a concomitant rise in PSA level [1205]. However, this has only been proven in patients with unfavourable undifferentiated tumours. Prostate-specific antigen measurement and DRE comprise the most useful combination for first-line examination in follow-up after RT but the role of DRE was questioned since it failed to detect any local recurrence in the absence of a rising PSA in a series of 899 patients [1206]. In a series of 1,118 prostatectomy patients, no local histologically proven recurrence was found by DRE alone and PSA measurement may be the only test needed after RP [1207, 1208]. 7.1.3.1.5 Transrectal ultrasound, bone scintigraphy, CT, MRI and PET/CT Imaging techniques have no place in routine follow-up of localised PCa as long as the PSA is not rising. Imaging is only justified in patients for whom the findings will affect treatment decisions, either in case of BCR or in patients with symptoms (see Section 6.3.4 for a more detailed discussion). 7.1.4 How long to follow-up? Most patients who fail treatment for PCa do so within 7 years after local therapy [482]. Patients should be followed up more closely during the initial post-treatment period when risk of failure is highest. Prostatespecific antigen measurement, disease-specific history and DRE (if considered) are recommended every 6 months until 3 years and then annually. Whether follow-up should be stopped if PSA remains undetectable (after RP) or stable (after RT) remains an unanswered question. 7.1.5

Summary of evidence and guidelines for follow-up after treatment with curative intent

Summary of evidence A rising PSA must be differentiated from a clinically meaningful relapse. The PSA threshold that best predicts further metastases after RP is > 0.4 ng/mL and > NADIR + 2 after IMRT plus IGRT (± ADT]. Palpable nodules combined with increasing serum PSA suggest at least local recurrence.

Recommendations Routinely follow up asymptomatic patients by obtaining at least a disease-specific history and serum prostate-specific antigen (PSA) measurement. These should be performed at 3, 6 and 12 months after treatment, then every 6 months until 3 years, and then annually. At recurrence, only perform imaging if the result will affect treatment planning.

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Follow-up: During first line hormonal treatment (androgen sensitive period)

7.2.1 Introduction Androgen deprivation therapy is used in various situations: combined with radiotherapy for localised or locally-advanced disease, as monotherapy for a relapse after a local treatment, or in the presence of metastatic disease often in combination with other treatments. All these situations are based on the benefits of testosterone suppression either by drugs (LHRH agonists or antagonists) or orchidectomy. Inevitably, the disease will become castrate-resistant, although ADT will be maintained. This paragraph addresses the general principles of follow-up of patients on ADT alone. As treatment of CRPC and follow-up are closely linked, Section 6.5.7 includes further information on other drug treatments. Furthermore the specific follow-up needed for every single drug is outside the scope of this text. Regular clinical follow-up is mandatory and cannot be replaced by imaging or laboratory tests alone. Complementary investigations must be restricted to those that are clinically helpful to avoid unnecessary examinations and costs. 7.2.2 Purpose of follow-up The main objectives of follow-up in patients receiving ADT are to ensure treatment compliance, to monitor treatment response, to detect side effects early, and to guide treatment at the time of CRPC. After the initiation of ADT, it is recommended that patients are evaluated every 3 to 6 months. This must be individualised and each patient should be advised to contact his physician in the event of troublesome symptoms.

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7.2.3 General follow-up of men on ADT Patients under ADT require regular follow-up, including monitoring of serum testosterone, creatinine, liver function and metabolic parameters at 3 to 6 month intervals. Men on ADT can experience toxicity independent of their disease stage. 7.2.3.1 Testosterone monitoring Testosterone monitoring should be considered standard clinical practice in men on ADT. Many men receiving medical castration will achieve a castrate testosterone level (< 20 ng/dL), and most a testosterone level < 50 ng/dL. However, approximately 13–38% of patients fail to achieve these levels and up to 24% of men may experience temporary testosterone surges (testosterone > 50 ng/dL) during long-term treatment [1200] referred to as ‘acute on-chronic effect’ or ‘breakthrough response’ [1209]. Breakthrough rates for the < 20 ng/dL threshold were found to be more frequent (41.3%) and an association with worse clinical outcomes was suggested [1209]. The timing of measurements is not clearly defined. A 3 to 6-month testosterone level assessment has been suggested to ensure castration is achieved (especially during medical castration) and maintained. In case the castrate testosterone level is not reached, switching to another agonist or antagonist or to an orchiectomy should be considered. In patients with a confirmed rising PSA and/or clinical progression, serum testosterone must be evaluated in all cases to confirm a castration-resistant state. Ideally, suboptimal testosterone castrate levels should be confirmed with mass spectrometry or an immunoassay [1210, 1211]. 7.2.3.2 Liver function monitoring Liver function tests will detect treatment toxicity (especially applicable for NSAA), but rarely indicate disease progression. Men on combined ADT should have their transaminase levels checked at least twice a year in view of potential liver toxicity but a more frequent check is needed with some drugs (like abiraterone acetate). Alkaline phosphatase may increase secondary to bone metastases and androgen-induced osteoporosis, therefore it may be helpful to determine bone-specific isoenzymes as none are directly influenced by ADT [1212]. 7.2.3.3 Serum creatinine and haemoglobine Estimated glomerular filtration rate monitoring is good clinical practice as an increase may be linked to ureteral obstruction or bladder retention. A decline in Hb is a known side effect of ADT. A significant decline after 3 months of ADT is independently associated with shorter progression-free and OS rates and might explain significant fatigue although other causes should be considered [1213]. Anaemia is often multi-factorial and other possible aetiologies should be excluded. 7.2.3.4 Monitoring of metabolic complications The most severe complications of androgen suppression are metabolic syndrome, cardiovascular morbidity, mental health problems, and bone resorption (see Section 8.2.4.5). All patients should be screened for diabetes by checking fasting glucose and HbA1c (at baseline and routinely) in addition to checking blood lipid levels. Men with impaired glucose tolerance and/or diabetes should be referred for an endocrine consultation. Prior to starting ADT a cardiology consultation should be considered in men with a history of cardiovascular disease and in men older than 65 years. Men on ADT are at increased risk of cardiovascular problems and hypertension and regular checks are required [1214]. 7.2.3.5 Monitoring bone problems Androgen deprivation therapy increases the risk of osteoporosis. Adminstration of ADT for more than a year, as compared to less than one year, showed a higher risk of osteoperosis (HR: 1.77 and 1.38, respectively) [1215]. Several scores (e.g., Fracture Risk Assessment Tool [FRAX score], Osteoporosis Self-Assessment Tool [OST], Osteoporosis Risk Assessment Instrument [ORAI], Osteoporosis Index of Risk [OSIRIS], Osteoporosis Risk Estimation [SCORE]) can help identify men at risk of osteoporotic complications but validation of these scores in the ADT setting is required (see Section 8.3.2.2) [1216-1218]. Routine bone monitoring for osteoporosis should be performed using DEXA scan [1219-1221]. Presence of osteoporosis should prompt the use of bone protective agents. The criteria for initiation of bone protective agents are mentioned in Section 8.3.2.2. If no bone protective agents are given, a DEXA scan should be done regularly, at least every 2 years [1222] A review summarising the incidence of bone fractures showed an almost doubling of the risk of fractures when using ADT depending on patients’ age and duration and type of ADT with the highest incidence in older men and men on additional novel ARTA medication across the entire spectrum of disease [1223]. In case of an osteoporotic fracture a bone protective agent is mandatory. Vitamin D and calcium levels should be regularly monitored when patients receive ADT and patients should be supplemented if needed. (see Section 6.5.15).

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7.2.3.6 Monitoring lifestyle and cognition Lifestyle (e.g., diet, exercise, smoking status, etc.) affects QoL and potentially outcome [1212, 1213]. During follow-up men should be counselled on the beneficial effects of exercise to avoid ADT-related toxicity [1224]. Androgen deprivation therapy may affect mental and cognitive health and men on ADT are three times more likely to report depression [1225]. Attention to mental health should therefore be an integral part of the followup scheme. 7.2.4 Methods of follow-up in men on ADT without metastases 7.2.4.1 Prostate-specific antigen monitoring Prostate-specific antigen is a key marker for following the course of androgen-sensitive non-metastasised PCa. Imaging should be considered when PSA is rising > 2 ng/mL or in case of symptoms suggestive of metastasis. 7.2.4.2 Imaging In general, asymptomatic patients with a stable PSA level do not require further imaging, although care needs to be taken in patients with aggressive variants when PSA levels may not reflect tumour progression [1226]. New bone pain requires at least targeted imaging and potentially a bone scan. When PSA progression suggests CRPC status and treatment modification is considered, imaging, by means of a bone and CT scan, is recommended for restaging. Detection of metastases greatly depends on imaging (see Section 6.3.4). 7.2.5 Methods of follow-up in men under ADT for metastatic hormone-sensitive PCa In metastatic patients it is of the utmost importance to counsel about early signs of spinal cord compression, urinary tract complications (ureteral obstruction, bladder outlet obstruction) or bone lesions that are at an increased fracture risk. The intervals for follow-up in M1 patients should be guided by patients’ complaints and can vary. Since most men will receive another anti-cancer therapy combined with ADT such as ARTA, chemotherapy or local radiotherapy, follow-up frequency should also be dependent on the treatment modality. 7.2.5.1 PSA monitoring In men on ADT alone, a PSA decline to < 4 ng/mL suggests a likely prolonged response and follow-up visits may be scheduled every 3 to 6 months provided the patient is asymptomatic or clinically improving. Depending on symptoms and risk assessment, more frequent visits may be indicated. Treatment response may be evaluated based on a change in serum PSA level [1049, 1050] and bone- and CT scan although there is no consensus about how frequently these should be performed [1176]. A rise in PSA level usually precedes the onset of clinical symptoms by several months. A rising PSA should prompt assessment of testosterone level, which is mandatory to define CRPC status, as well as restaging using imaging. However it is now recognised that a stable PSA during ADT is not enough to characterise a non-progressive situation [1227]. 7.2.5.2 Imaging as a marker of response in metastatic PCa Treatment response in soft-tissue metastases can be assessed by morphological imaging methods using the Response Evaluation Criteria in Solid Tumours (RECIST) criteria. However, these criteria cannot be used in bone where response assessment is difficult [1228, 1229]. When bone scan is used to follow bone metastases, a quantitative estimation of tracer uptake at bone scan can be obtained through automated methods such as the Bone Scan Index [1230]. Nonetheless, bone scan is limited by the so-called ‘flare’ phenomenon which is defined by the development of new images induced by treatment on a first follow-up scan which, after longer observation, actually represent a favourable response. Flare is observed within 8 to 12 weeks of treatment initiation and can lead to a false-positive diagnosis of disease progression. Computed tomography cannot be used to monitor sclerotic bone lesions because bone sclerosis can occur under effective treatment and reflects bone healing. Magnetic resonance imaging can directly assess the bone marrow and demonstrate progression based on morphologic criteria or changes in apparent diffusion coefficient. A standardisation for reporting is available [1231]. The ability of PET/ CT to assess response has been evaluated in a few studies. Until further data are available, MRI and PET/CT should not be used outside trials for treatment monitoring in metastatic patients [1232]. Men with metastasised PCa on ADT should also in the absence of PSA rise be followed up with regular imaging since twenty-five percent of men on ADT in the ECOG3805 CHAARTED trial developed progression on imaging without a PSA rise [1227].

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7.2.6

Guidelines for follow-up during hormonal treatment

Recommendations The follow-up strategy must be individualised based on stage of disease, prior symptoms, prognostic factors and the treatment given. In patients with stage M0 disease, schedule follow-up at least every 6 months. As a minimum requirement, include a disease-specific history, serum prostate-specific antigen (PSA) determination, as well as liver and renal function in the diagnostic work-up. In M1 patients, schedule follow-up at least every 3 to 6 months. In patients on long-term androgen deprivation therapy (ADT), measure initial bone mineral density to assess fracture risk. During follow-up of patients receiving ADT, check PSA and testosterone levels and monitor patients for symptoms associated with metabolic syndrome as a side effect of ADT. As a minimum requirement, include a disease-specific history, haemoglobin, serum creatinine, alkaline phosphatase, lipid profiles and HbA1c level measurements. Counsel patients (especially with M1b status) about the clinical signs suggestive of spinal cord compression. When disease progression is suspected, restaging is needed and the subsequent follow-up adapted/individualised. In M1 patients perform regular imaging (CT and bone scan) even without PSA progression. In patients with suspected progression, assess the testosterone level. By definition, castration-resistant PCa requires a testosterone level < 50 ng/dL (< 1.7 nM/L).

8.

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QUALITY OF LIFE OUTCOMES IN PROSTATE CANCER

This chapter is presented in two parts. The first (8.2) will summarise long-term consequences (> 12 months) of therapies for PCa. Based on two systematic reviews, the second (8.3) provides evidence-based recommendations for supporting patients when selecting primary treatment options for localised disease and also supportive interventions aimed at improving disease-specific QoL across all stages of disease.

8.1

Introduction

Quality of life and personalised care go hand in hand. Treating PCa can affect an individual both physically and mentally, as well as close relations and work or vocation. These multifaceted issues all have a bearing on an individual‘s perception of QoL [1233]. Approaching care from a holistic point of view requires the intervention of a multi-disciplinary team including urologists, medical oncologists, radiation oncologists, oncology nurses, behavioural practitioners and many others including fellow patients. Attention to the psychosocial concerns of people with PCa is integral to quality clinical care, and this can include the needs of carers and partners [1234]. Prostate cancer care should not be reduced to focusing on the organ in isolation: side effects or late adverse effects of treatment can manifest systemically and have a major influence on the patient’s QoL. Taking QoL into consideration relies on understanding the patient’s values and preferences so that optimal treatment proposals can be formulated and discussed.

8.2

Adverse effects of PCa therapies

8.2.1 Surgery The absence of standardisation in reporting surgical complications for RP and the introduction of different techniques has resulted in a wide variation in the types of complications reported, as well as variation in the overall incidence of complications [1235-1238]. The most common post-operative issue is ED but other related issues to consider include dry ejaculation, which occurs with removal of the prostate, change in the quality of orgasm and occasional pain on orgasm. Men also complain of loss of penile length (3.73%, 19/510 men) [1239]. The second most commonly occurring complication is long-term incontinence [1235-1238] but voiding difficulties may also occur associated with bladder neck contracture (e.g., 1.1% after RALP) [1240]. For those undergoing minimally invasive procedures port site hernia has been reported in 0.66% after inserting 12 mm bladeless trocar [1241] and can occur more rarely with 8 mm and 5 mm trocars [1241]. A key consideration is whether long-term consequences of surgery are reduced by using newer techniques

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such as RALP. Systematic reviews have documented complication rates after RALP [500, 591-594], and can be compared with contemporaneous reports after RRP [595]. From these reports, the mean continence rates at 12 months were 89–100% for patients treated with RALP and 80–97% for patients treated with RRP. A prospective controlled non-randomised trial of patients undergoing RP in 14 centres using RALP or RRP demonstrated that at 12 months after RALP, 21.3% were incontinent, as were 20.2% after RRP. The unadjusted OR was 1.08 (95% CI: 0.87–1.34). Erectile dysfunction was observed in 70.4% after RALP and 74.7% after RRP. The unadjusted OR was 0.81 (95% CI: 0.66–0.98) [596, 1242]. Further follow-up demonstrates similar functional outcomes with both techniques at 24 months [1242, 1243]. A single-centre randomised phase III study comparing RALP and RRP (n = 326) also demonstrates similar functional outcomes with both techniques at 24 months [495]. 8.2.2 Radiotherapy 8.2.2.1 Side-effects of external beam radiotherapy Analysis of the toxicity outcomes of the Prostate Testing for Cancer and Treatment (ProtecT) trial [1244] shows that patients treated with EBRT and 6 months of ADT report bowel toxicity including persistent diarrhoea, bowel urgency and/or incontinence and rectal bleeding (described in detail in Section 8.3.1.1 below). Participants in the ProtecT study were treated with 3D-CRT and more recent studies using IMRT demonstrate less bowel toxicity than noted previously with 3D-CRT [1245]. A systematic review and meta-analysis of observational studies comparing patients exposed or unexposed to radiotherapy in the course of treatment for PCa demonstrates an increased risk of developing second cancers for bladder (OR: 1.39), colorectal (OR: 1.68) and rectum (OR: 1.62) with similar risks over lag times of 5 and 10 years. Absolute excess risks over 10 years are small (1–4%) but should be discussed with younger patients in particular [1246]. 8.2.2.2 Side effects from brachytherapy Some patients experience significant urinary complications following implantation such as urinary retention (1.5-22%), with post-implantation TURP reported as being required in up to 8.7% of cases, and incontinence (0–19%) [1247]. Chronic urinary morbidity is more common with combined EBRT and BT and can occur in up to 20% of patients, depending on the severity of the symptoms before brachytherapy. Urethral strictures account for at least 50% of urinary complications and can be resolved with dilation in the majority [822, 824]. Prevention of morbidity depends on careful patient selection, and expert assessment of IPSS score, backed up by urodynamic studies. 8.2.3 Local primary whole-gland treatments other than surgery or radiotherapy 8.2.3.1 Cryosurgery In Ramsay et al.’s systematic review and meta-analysis there was evidence that the rate of urinary incontinence at one year was lower for cryotherapy than for RP, but the size of the difference decreased with longer followup [758]. There was no significant difference between cryotherapy vs. EBRT in terms of urinary incontinence at one year (< 1%); cryotherapy had a similar ED rate (range 0–40%) to RP at one year. There were insufficient data to compare cryotherapy vs. EBRT in terms of ED. 8.2.3.2 High-intensity focused ultrasound In terms of toxicity there are insufficient data on urinary incontinence, ED or bowel dysfunction to draw any conclusions, although at one year HIFU had lower incontinence rates than RP (OR: 0.06, 95% CI: 0.01–0.48) [758]. 8.2.4 Hormonal therapy A summary of impacts on psychological factors due to the use of ADT such as sexual function, mood, depression, cognitive function and impact on partners can be found in two clinical reviews [1248, 1249]. A small RCT evaluated the QoL at one-year follow-up in patients with non-localised PCa, between various ADT regimens, or no treatment. Patients treated by ADT reported a significant decline in spatial reasoning, spatial abilities and working memory as well as increased depression, tension, anxiety, fatigue and irritability during treatment [1250]. Conversely, a prospective observational study with follow-up to 3 years failed to demonstrate an association with cognitive decline in men on ADT when compared to men with PCa not treated with ADT and healthy controls [1251]. A prospective observational study of non-metastatic PCa found that immediate ADT was associated with a lower overall QoL compared to deferred treatment [1252]. Another retrospective non-randomised study suggested that men receiving LHRH agonists reported more worry and physical discomfort and poorer overall health, and were less likely to believe themselves free of cancer than patients undergoing orchiectomy. The stage at diagnosis had no effect on health outcomes [1253]. Using a specific non-validated questionnaire, bicalutamide monotherapy showed a significant advantage over castration in the domains of physical capacity and sexual interest (not sexual function) at

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12 months [1254]. A post-hoc analysis, including only patients with sexual interest suggested that bicalutamide was associated with better sexual preservation, including maintained sexual interest, feeling sexually attractive [1255], preserved libido and erectile function [1256]. Intermittent androgen deprivation has been discussed elsewhere (see Section 6.4.3.2). 8.2.4.1 Sexual function Cessation of sexual activity is very common in people undergoing ADT, affecting up to 93% [1257]. Androgen deprivation therapy reduces both libido and the ability to gain and maintain erections. The management of acquired ED is mostly non-specific [1258]. 8.2.4.2 Hot flushes Hot flushes are a common side-effect of ADT (prevalence estimated between 44–80% of men on ADT) [1257]. They appear 3 months after starting ADT, usually persist long-term and have a significant impact on QoL. Oestrogen-receptor modulators or low-dose oestrogen therapies, e.g. DES, 0.5–1 mg/day, reduce the frequency and severity of hot flushes. Both treatments carry a risk of cardiovascular complications [1259]. Serotonin re-uptake inhibitors (e.g., venlafaxine or sertraline) also appear to be effective in men but less than hormone therapies based on a prospective RCT comparing venlafaxine, 75 mg daily, with medroxyprogesterone, 20 mg daily, or cyproterone acetate, 100 mg daily [1260]. After 6 months of LHRH (n = 919), 311 men had significant hot flushes and were randomised to one of the treatments. Based on median daily hot-flush score, venlafaxine was inferior -47.2% (interquartile range -74.3 to -2.5) compared to -94.5% (-100.0 to -74.5) in the cyproterone group, and -83.7% (-98.9 to -64.3) in the medroxyprogesterone group. With a placebo effect influencing up to 30% of patients [1261], the efficacy of clonidine, veralipride, gabapentine [1262] and acupuncture [1263] need to be compared in prospective RCTs. 8.2.4.3 Non-metastatic bone fractures Due to increased bone turnover and decreased bone mineral density (BMD) in a time-dependent manner, ADT use is linked to an increased risk of fracture (up to 45% RR with long-term ADT) [1264]. Severe fractures in men are associated with a significant risk of death [1265]. A precise evaluation of BMD should be performed by dual emission X-ray absorptiometry (DEXA), ideally before or shortly after starting long-term ADT. An initial low BMD (T-score < -2.5 or < -1, with other risk factors) indicates a high risk of subsequent non-metastatic fracture and causes should be investigated. Other risk factors include increasing age, body mass index of 19 or less, history of previous fracture or parent with fractured hip, current smoking, use of glucocorticoids, rheumatoid arthritis, alcohol consumption > 2 units per day, history of falls and a number of other chronic medical conditions [1266]. Fracture risk alorithms which combine BMD and clinical risk factors such as FRAX score can be used to guide treatment decisions but uncertainty exists regarding the optimal intervention threshold, therefore no specific risk algorithm can be recommended for men on ADT for PCa. Obesity (increase in body fat mass by up to 10%) and sarcopenia (decrease in lean tissue mass by up to 3%) as well as weight loss are common and occur during the first year of ADT [1267]. These changes increase the fracture risk [1268]. Bicalutamide monotherapy may have less impact on BMD but is limited by its suboptimal efficacy [1269, 1270] (see Section 6.1.4.1.1.5.2.3). The intermittent LHRH-agonist modality might be associated with less bone impact [1271]. 8.2.4.4 Metabolic effects Lipid alterations are common and may occur as early as the first 3 months of treatment [1267]. Androgen deprivation therapy also decreases insulin sensitivity and increases fasting plasma insulin levels, which is a marker of insulin resistance. In diabetic patients, metformin appears to be an attractive option for protection against metabolic effects based on retrospective analysis [1272], but there is insufficient data to recommend its use in non-diabetic patients. Metabolic syndrome is an association of independent cardiovascular disease risk factors, often associated with insulin resistance. The definition requires at least three of the following criteria [1273]: • waist circumference > 102 cm; • serum triglyceride > 1.7 mmol/L; • blood pressure > 130/80 mmHg or use of medication for hypertension; • high-density lipoprotein (HDL) cholesterol < 1 mmol/L; • glycaemia > 5.6 mmol/L or the use of medication for hyperglycaemia. The prevalence of a metabolic-like syndrome is higher during ADT compared with men not receiving ADT [1274].

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Skeletal muscle mass heavily influences basal metabolic rate and is in turn heavily influenced by endocrine pathways [1275]. Androgen deprivation therapy-induced hypogonadism results in negative effects on skeletal muscle health. A prospective longitudinal study involving 252 men on ADT for a median of 20.4 months reported lean body mass decreases progressively over 3 years; 1.0% at one year, 2.1% at 2 years, and 2.4% at 3 years which appears more pronounced in men at > 70 years of age [1276]. 8.2.4.5 Cardiovascular morbidity Cardiovascular mortality is a common cause of death in PCa patients [1040, 1277, 1278]. Several studies showed that ADT after only 6 months was associated with an increased risk of diabetes mellitus, cardiovascular disease, and myocardial infarction [1279]. The RTOG 92-02 [1280] and 94-08 [1281] trials confirmed an increased cardiovascular risk, unrelated to the duration of ADT and not accompanied by an overall increased cardiovascular mortality. No increase in cardiovascular mortality has been reported in a systematic meta-analysis of trials RTOG 8531, 8610, 9202, EORTC 30891 or EORTC 22863 [1282]. However, serious concerns about the conclusions of this meta-analysis have been raised due to poor consideration of bias in the included studies [1283, 1284]. Meta-analysis of observational data reports consistent links between ADT and the risk of cardiovascular disease patients treated for PCa e.g. the associations between GnRH agonists and nonfatal or fatal myocardial infarction or stroke RR: 1.57 (95% CI: 1.26–1.94) and RR: 1.51 (95% CI: 1.24–1.84), respectively [1285]. An increase in cardiovascular mortality has been reported in patients suffering from previous congestive heart failure or myocardial infarction in a retrospective database analysis [1286] or presenting with a metabolic syndrome [1287]. It has been suggested that LHRH antagonists might be associated with less cardiovascular morbidity compared to agonists [1288]. In a phase III RCT the use of relugolix, an oral LHRH antagonist, was associated with a reduced risk of major adverse cardiovascular events when compared to leuprolide, an injectable LHRH agonists, at 2.9% vs. 6.2%, respectively, over a follow-up time of of 48 weeks (HR 0.46, 95% CI: 0.24–0.88 [727]. These concerns resulted in an FDA warning and consensus paper from the American Heart, Cancer Society and Urological Associations [1039]. Preventive advice includes non-specific measures such as loss of weight, increased exercise, minimising alcohol intake, improved nutrition and smoking cessation [69, 1289]. 8.2.4.6 Fatigue Fatigue often develops as a side-effect of ADT. Regular exercise appears to be the best protective measure. Anaemia may be a cause of fatigue [1257, 1290]. Anaemia requires an aetiological diagnosis (medullar invasion, renal insufficiency, iron deficiency, chronic bleeding) and individualised treatment. Iron supplementation (using injectable formulations only) must be systematic if deficiency is observed. Regular blood transfusions may be required in patients with severe anaemia. Erythropoiesis-stimulating agents might be considered in dedicated cases, taking into account the possible increased risk of thrombovascular events [1291]. 8.2.4.7 Neurological side effects Castration seems also to be associated with an increased risk of stroke [1292], and is suspect to be associated with an increased risk for depression and cognitive decline such as Alzheimer disease [1293].

8.3

Overall quality of life in men with PCa

Living longer with PCa does not necessarily equate to living well [1233, 1234]. There is clear evidence of unmet needs and ongoing support requirements for some individuals after diagnosis and treatment for PCa [1294]. Cancer impacts on the wider family and cognitive behavioural therapy can help reduce depression, anxiety and stress in caregivers [1295]. Radical treatment for PCa can negatively impact long-term QoL (e.g., sexual, urinary and bowel dysfunction) as can ADT used in short- or long-term treatment, e.g., sexual problems, fatigue, psychological morbidity, adverse metabolic sequelae and increased cardiovascular and bone fracture risk [1248, 1296]. Direct symptoms from advanced or metastatic cancer, e.g., pain, hypercalcaemia, spinal cord compression and pathological fractures, also adversely affect health [1297, 1298]. Patient’s QoL including domains such as sexual function, urinary function and bowel function is worse after treatment for PCa compared to non-cancer controls [1299, 1300]. The concept of ‘quality of life’ is subjective and can mean different things to different people, but there are some generally common features across virtually all patients. Drawing from these common features, specific tools or ‘patient-reported outcome measures’ (PROMs) have been developed and validated for men with PCa. These questionnaires assess common issues after PCa diagnosis and treatment and generate scores which reflect the impact on perceptions of HRQoL. During the process of undertaking two dedicated systematic reviews around cancer-specific QoL outcomes in patients with PCa as the foundation for our guideline recommendations, the following validated PROMs were found in our searches (see Table 8.3.1).

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Table 8.3.1: PROMs assessing cancer specific quality of life Questionnaire Functional Assessment of Cancer Therapy-General (FACT-G) [1301] Functional Assessment of Cancer Therapy-Prostate (FACT-P) [1302]

Domains/items Physical well-being, social/family well-being, emotional well-being, and functional well-being. 12 cancer site specific items to assess for prostate-related symptoms. Can be combined with FACT-G or reported separately. European Organisation for Research and Treatment of Five functional scales (physical, role, cognitive, Cancer QLQ-C30 (EORTC QLQ-C30) [1303] emotional, and social); three symptom scales (fatigue, pain, and nausea and vomiting); global health status/QoL scale; and a number of single items assessing additional symptoms commonly reported by cancer patients (dyspnoea, loss of appetite, insomnia, constipation and diarrhoea) and perceived financial impact of the disease. European Organisation for Research and Treatment of Urinary, bowel and treatment-related symptoms, Cancer QLQ-PR 25 (EORTC QLQ-PR 25) [1304] as well as sexual activity and sexual function. Expanded prostate cancer index composite (EPIC) [1305] Urinary, bowel, sexual, and hormonal symptoms. Expanded prostate cancer index composite short form Urinary, sexual, bowel, and hormonal domains. 26 (EPIC 26) [1306] UCLA Prostate Cancer Index (UCLA PCI) [1307] Urinary, bowel, and sexual domains. Prostate Cancer Quality of Life Instrument (PCQoL) Urinary, sexual, and bowel domains, supplemented [1308] by a scale assessing anxiety. Prostate Cancer Outcome Study Instrument [1309] Urinary, bowel, and sexual domains. 8.3.1 Long-term (> 12 months) quality of life outcomes in men with localised disease 8.3.1.1 Men undergoing local treatments The results of the Prostate Testing for Cancer and Treatment (ProtecT) trial (n = 1,643 men) reported no difference in EORTC QLQ-C30 assessed global QoL, up to 5 years of follow-up in men aged 50–69 years with T1-T2 disease randomised for treatment with AM, RP or RT with 6 months of ADT [1244]. However, EPIC urinary summary scores (at 6 years) were worse in men treated with RP compared to AM or RT (88.7 vs. 89.0 vs. 91.4, respectively) as were urinary incontinence (80.9 vs. 85.8 vs. 89.4, respectively) and sexual summary, function and bother scores (32.3 vs. 40.6 vs. 41.3 for sexual summary, 23.7 vs. 32.5 vs. 32.7 for sexual function and 51.4 vs. 57.9 vs. 60.1 for sexual bother, respectively) at 6 years of follow-up. Minimal clinically important differences for the 50 item EPIC questionnaire are not available. For men receiving RT with 6 months of ADT, EPIC bowel scores were poorer compared to AM and RP in all domains: function (90.8 vs. 92.3 vs. 92.3, respectively), bother (91.7 vs. 94.2 vs. 93.7, respectively) and summary (91.2 vs. 93.2 vs. 93.0, respectively) at 6 years of follow-up in the ProtecT trial. The findings regarding RP and RT are supported by other observational studies [1238, 1310]. The Prostate Cancer Outcomes Study (PCOS) [1238] studied a cohort of 1,655 men, of whom 1,164 had undergone RP and 491 RT. The study reported that at 5 years of follow-up, men who underwent RP had a higher prevalence of urinary incontinence and ED, while men treated with RT had a higher prevalence of bowel dysfunction. However, despite these differences detected at 5 years, there were no significant differences in the adjusted odds of urinary incontinence, bowel dysfunction or ED between RP and RT at 15 years. More recently, investigators reported that although EBRT was associated with a negative effect in bowel function, the difference in bowel domain score was below the threshold for clinical significance 12 months after treatment [1245]. As 81% of patients in the EBRT arm of the study received IMRT, these data suggest that the risk of side effects is reduced with IMRT compared to older 3D-CRT techniques. This is supported by a contemporary 5-year prospective, population-based cohort study where PROs were compared in men with favourable- and unfavourable-risk localised disease [1310]. In the 1,386 men with favourable risk, comparison between AS and nerve-sparing prostatectomy, EBRT or LDR brachytherapy demonstrates that surgery is associated with worse urinary incontinence at 5 years and sexual dysfunction at 3 years when compared to AS. External beam RT is associated with changes not clinically different from AS, and LDR brachytherapy is associated with worse irritative urinary-, bowel- and sexual symptoms at one year. In 619 men with unfavourable risk disease, comparison between non-nerve sparing RP and EBRT with ADT demonstrates that surgery is associated with worse urinary incontinence and sexual function through 5 years.

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With respect to brachytherapy cancer-specific QoL outcomes, one small RCT (n = 200) evaluated bilateral nerve-sparing RP and brachytherapy in men with localised disease (up to T2a), which reported worsening of physical functioning as well as irritative urinary symptomatology in 20% of brachytherapy patients at one year of follow-up. However, there were no significant differences in EORTC QLQ-C30/PR-25 scores at 5 years of follow-up when compared to pre-treatment values [1311]. It should be noted of this trial, within group tests only were reported. In a subsequent study by the same group comparing bilateral nerve-sparing RARP and brachytherapy (n = 165), improved continence was noted with brachytherapy in the first 6 months but lower potency rates up to 2 years [1312]. These data and a synthesis of 18 randomised and non-randomised studies in a systematic review involving 13,604 patients are the foundation of the following recommendations [1313]. 8.3.1.2

Guidelines for quality of life in men undergoing local treatments

Recommendations Advise eligible patients for active surveillance that global quality of life is equivalent for up to 5 years compared to radical prostatectomy or external beam radiotherapy. Discuss the negative impact of surgery on urinary and sexual function, as well as the negative impact of radiotherapy on bowel function with patients. Advise patients treated with brachytherapy of the negative impact on irritative urinary symptomatology at one year but not after 5 years.

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8.3.2 Improving quality of life in men who have been diagnosed with PCa 8.3.2.1 Men undergoing local treatments In men with localised disease, nurse-led multi-disciplinary rehabilitation (addressing sexual functioning, cancer worry, relationship issues depression, managing bowel and urinary function problems) provided positive shortterm effects (4 months) on sexual function (effect size 0.45) and long-term (12 months) positive effects on sexual limitation (effect size 0.5) and cancer worry (effect size 0.51) [1314]. In men with post-surgical urinary incontinence, conservative management options include pelvic floor muscle training with or without biofeedback, electrical stimulation, extra-corporeal magnetic innervation (ExMI), compression devices (penile clamps), lifestyle changes, or a combination of methods. Uncertainty around the effectiveness and value of these conservative interventions remains [1315]. Surgical interventions including sling and artificial urinary sphincter significantly decrease the number of pads used per day and increase the QoL compared with before intervention. The overall cure rate is around 60% and results in improvement in incontinence by about 25% [1316]. The use of PDE5 inhibitors in penile rehabilitation has been subject to some debate. A single centre, double blind RCT of 100 men undergoing nerve-sparing surgery reported no benefit of nightly sildenafil (50 mg) compared to on-demand use [1317]. However, a multi-centre double blind RCT (n = 423) in men aged < 68 years, with normal pre-treatment erectile function undergoing either open, conventional or robot-assisted laparoscopic nerve-sparing RP, tadalafil (5 mg) once per day improved participants EPIC sexual domain-scores (least squares mean difference +9.6, 95% CI: 3.1–16.0) when compared to 20 mg ‘on demand’ or placebo at 9 months of follow-up [622]. Therefore, based on discordant results, no clear recommendation is possible, even if a trend exists for early use of PDE5 inhibitors after RP for penile rehabilitation [1318]. A detailed discussion can be found in the EAU Sexual and Reproductive Health Guidelines [1319]. 8.3.2.2 Men undergoing systemic treatments Similar to men treated with a radical approach (see above), in men with T1-T3 disease undergoing RT and ADT, a combined nurse-led psychological support and physiotherapist-led multi-disciplinary rehabilitation has reported improvements in QoL. Specifically this intervention involved action planning around patients’ needs related to lifestyle changes, weight control, toilet habits, sexuality, and psychological problems. This was complemented with pelvic floor muscle therapy. Improvements in urinary (adjusted mean 4.5, 95% CI: 0.6–8.4), irritative (adjusted mean 5.8, 95% CI: 1.4–10.3) and hormonal (adjusted mean 4.8, 95% CI: 0.8–8.8) EPIC domains were found up to 22 weeks of follow-up [1320]. Providing supervised aerobic and resistance exercise training of a moderate intensity improves EORTC QLQ-C30 role (adjusted mean 15.8, 95% CI: 6.6–24.9) and cognitive domain outcomes (adjusted mean 11.4, 95% CI: 3.3–19.6) as well as symptom scales for fatigue (adjusted mean 11.0, 95% CI: 20.2–1.7), nausea (adjusted mean 4.0, 95% CI: 7.4–0.25), and dyspnoea (adjusted mean 12.4, 95% CI: 22.5–2.3) up to 3 months in men treated with ADT [1321]. Such interventions have also reported clinically relevant improvements in FACT-P (mean difference 8.9, 95% CI: 3.7–14.2) in men on long-term ADT [1322, 1323]. These findings are supported by a systematic review which reported improvements up to 12 weeks in cancer-specific QoL in a meta-analysis of high quality trials (SMD 0.33, 95%, CI: 0.08–0.58) [1290].

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In case dietary intake is not adequate, vitamin D and calcium supplementation should be offered, as there is evidence that vitamin D and calcium have modest effects on bone in men on ADT [1324]. Online tools are available to calculate daily calcium intake for individual patients. For vitamin D deficiency a dose of at least 800 IU/day colecalciferol can be recommended. Use of a 25(OH) assay may be helpful to measure vitamin D levels [1325, 1326]. Anti-resorptive therapy is recommended for men on ADT for > 6 months with either a BMD T score of < -2.5 or with an additional risk factor for osteoporosis or annual bone loss confirmed to exceed 5%, or in cases of severe fracture. Referral to a bone specialist should be considered in complex cases with severe fracture and/or multiple risk factors. Alendronate, risedronate, zoledronate and denosumab have all been shown to prevent bone loss in men with locally-advanced PCa on ADT [1222, 1327-1329]. Patients should be warned about the < 5% risk of osteonecrosis of the jaw and/or atypical femoral fractures associated with these drugs. Bisphosphonates increase BMD in the hip and spine by up to 7% in one year [1328, 1330]. The optimal regimen for zoledronic acid remains unclear: quarterly [1331] or yearly [1332] injections. The question is relevant as the risk of jaw necrosis is both dose- and time-related [1333]. A quarterly regimen could be considered for a BMD < 2.5 as a yearly injection is unlikely to provide sufficient protection [1334]. Care should be taken when discontinuing treatment as rebound increased bone resorption can occur. In M0 patients, denosumab has been shown to increase the lumbar BMD by 5.6% compared to a 1% decrease in the placebo arm after 2 years, using a 60 mg subcutaneous regimen every 6 months [1335]. This was associated with a significant decrease in vertebral fracture risk (1.5% vs. 3.9%, p = 0.006). The benefits were similar whatever the age (< or > 70 years), the duration or type of ADT, the initial BMD, the patient’s weight or the initial BMI. This benefit was not associated with any significant toxicity, e.g. jaw osteonecrosis or delayed healing in vertebral fractures. In M0 patients, with the use of a higher dosage (120 mg every 4 weeks), a delay in bone metastases of 4.2 months has been shown [1187] without any impact on OS, but with an increase in side effects. Therefore, this later regimen cannot be recommended. 8.3.2.3 Decision regret Several treatments with curative intent for localised PCa are available all with comparable 10-year OS [467]. They vary in terms of the incidence of major side effects, including urinary symptoms, bowel symptoms and compromised sexual functioning [1244, 1245, 1336]. For this reason, patients’ treatment preferences, in which they weigh expected benefits against likely side effects, are a central consideration in shared decision-making and in making informed treatment decisions [1337-1339]. It remains challenging, however, to evaluate whether the decision-making process can be viewed as successful; that is, whether the choice of treatment best reflects the patient’s preferences and expectations [1340, 1341]. According to Decision Justification Theory (DJT), it is the more specific information on which treatment experiences lead to regret that decision regret needs to be better understood and to minimise it in future patients [1342]. Maguire et al. found that about 25% of men with PCa undergoing either single or combined modality treatments report experiencing worse side effects than expected [1343]. Schroeck et al. found urinary incontinence most strongly correlated with regret after prostatectomy [1344]. Unmet expectations are comparable among the treatment groups, except for fatigue. Fatigue is less frequently reported as worse than expected by patients who received BT when compared to patients who received RP or EBRT. This could be explained by the less invasive treatment course of BT in comparison to EBRT with or without ADT and RP [1345]. Unmet expectations were more frequently reported by patients with positive surgical margins following surgery; having had a passive role in the decision-making process; and who had higher scores on the decisional conflict scale (i.e. more uncertainty about the treatment decision). Interestingly, positive surgical margins are not directly associated with an increased risk of PC-related mortality [969]. Active participation and support in the process of forming a preference increases the chance of choosing a treatment that is in line with patients’ expectations [1339, 1346, 1347]. While it may seem desirable to tailor the patients’ role in decision-making to their initial preference, and particularly to a preference for deferring to the advice of the clinician, this does not result in less decisional conflict or regret. Increasing patients knowledge regardless of initial preference may actually be preferable [1344]. 8.3.2.4 Decision aids in prostate cancer Shared decision-making can increase patients’ comfort when confronted with management decisions but has been shown to improve health outcome [1348] and more training seems needed for health care professionals guiding patients [1349]. Patient education decreased PSA testing [1350] and increased adherence to active surveillance protocols [1351, 1352]. Autonomous active decision-making by patients was associated with less regret after prostatectomy regardless of the method chosen and decision aids reduce decisional conflict [1353]. Still guidance is needed to optimise patients’ understanding of the options [1354]. Patients prioritised

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effectiveness and pain control over mode of administration and risk of fatigue when confronted with treatment choice in metastasised PCa [1355]. When implementing decision aids clinical validity and utility should be carefully evaluated and distinguished [1356]. A decision aid should educate as well as promote shared decision-making to optimise efficacy [1357] and pay attention to communicative aspects [1358]. 8.3.2.5

Guidelines for quality of life in men undergoing systemic treatments

Recommendations Offer men on androgen deprivation therapy (ADT), 12 weeks of supervised (by trained exercise specialists) combined aerobic and resistance exercise. Advise men on ADT to maintain a healthy weight and diet, to stop smoking, reduce alcohol to < 2 units daily and have yearly screening for diabetes and hypercholesterolemia. Ensure that calcium and vitamin D meet recommended levels. Offer men with T1-T3 disease specialist nurse-led, multi-disciplinary rehabilitation based on the patients’ personal goals addressing incontinence, sexuality, depression and fear of recurrence, social support and positive lifestyle changes after any radical treatment. Offer men starting on long-term ADT dual emission X-ray absorptiometry (DEXA) scanning to assess bone mineral density. Offer anti-resorptive therapy to men on long term ADT with either a BMD T-score of < -2.5 or with an additional clinical risk factor for fracture or annual bone loss on ADT is confirmed to exceed 5%.

Strength rating Strong Strong

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Salonia, A., et al., EAU Guidelines on Sexual and Reproductive Health, Edn. presented at the 36th Annual Congress, Milan. EAU Guidelines Office, Arnhem, The Netherlands. https://uroweb.org/guideline/sexual-and-reproductive-health/ Dieperink, K.B., et al. The effects of multidisciplinary rehabilitation: RePCa-a randomised study among primary prostate cancer patients. Br J Cancer, 2013. 109: 3005. https://pubmed.ncbi.nlm.nih.gov/3859951 Galvao, D.A., et al. Combined resistance and aerobic exercise program reverses muscle loss in men undergoing androgen suppression therapy for prostate cancer without bone metastases: a randomized controlled trial. J Clin Oncol, 2010. 28: 340. https://pubmed.ncbi.nlm.nih.gov/19949016 Bourke, L., et al. Lifestyle changes for improving disease-specific quality of life in sedentary men on long-term androgen-deprivation therapy for advanced prostate cancer: a randomised controlled trial. European urology, 2014. 65: 865. https://pubmed.ncbi.nlm.nih.gov/24119318 Cella, D., et al. Estimating clinically meaningful changes for the Functional Assessment of Cancer Therapy--Prostate: results from a clinical trial of patients with metastatic hormone-refractory prostate cancer. Value Health, 2009. 12: 124. https://pubmed.ncbi.nlm.nih.gov/18647260 Skolarus, T.A., et al. Androgen-deprivation-associated bone disease. Curr Opin Urol, 2014. 24: 601. https://pubmed.ncbi.nlm.nih.gov/25144145 Nair-Shalliker, V., et al. Post-treatment levels of plasma 25- and 1,25-dihydroxy vitamin D and mortality in men with aggressive prostate cancer. Sci Rep, 2020. 10: 7736. https://pubmed.ncbi.nlm.nih.gov/32385370 Grant, W.B. Review of Recent Advances in Understanding the Role of Vitamin D in Reducing Cancer Risk: Breast, Colorectal, Prostate, and Overall Cancer. Anticancer Res, 2020. 40: 491. https://pubmed.ncbi.nlm.nih.gov/31892604 Shapiro, C.L., et al. Management of Osteoporosis in Survivors of Adult Cancers With Nonmetastatic Disease: ASCO Clinical Practice Guideline. J Clin Oncol, 2019. 37: 2916. https://pubmed.ncbi.nlm.nih.gov/31532726 Briot, K., et al. French recommendations for osteoporosis prevention and treatment in patients with prostate cancer treated by androgen deprivation. Joint Bone Spine, 2019. 86: 21. https://pubmed.ncbi.nlm.nih.gov/30287350 Saylor, P.J., et al. Bone Health and Bone-Targeted Therapies for Prostate Cancer: ASCO Endorsement of a Cancer Care Ontario Guideline. J Clin Oncol, 2020. 38: 1736. https://pubmed.ncbi.nlm.nih.gov/31990618 Brown, J.E., et al. Guidance for the assessment and management of prostate cancer treatmentinduced bone loss. A consensus position statement from an expert group. J Bone Oncol, 2020. 25: 100311. https://pubmed.ncbi.nlm.nih.gov/32995252 Smith, M.R., et al. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol, 2003. 169: 2008. https://pubmed.ncbi.nlm.nih.gov/12771706 Michaelson, M.D., et al. Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer. J Clin Oncol, 2007. 25: 1038. https://pubmed.ncbi.nlm.nih.gov/17369566 Migliorati, C.A., et al. Bisphosphonate-associated osteonecrosis: a long-term complication of bisphosphonate treatment. Lancet Oncol, 2006. 7: 508. https://pubmed.ncbi.nlm.nih.gov/16750501 Wadhwa, V.K., et al. Frequency of zoledronic acid to prevent further bone loss in osteoporotic patients undergoing androgen deprivation therapy for prostate cancer. BJU Int, 2010. 105: 1082. https://pubmed.ncbi.nlm.nih.gov/19912210 Smith, M.R., et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med, 2009. 361: 745. https://pubmed.ncbi.nlm.nih.gov/19671656 Chen, R.C., et al. Association Between Choice of Radical Prostatectomy, External Beam Radiotherapy, Brachytherapy, or Active Surveillance and Patient-Reported Quality of Life Among Men With Localized Prostate Cancer. Jama, 2017. 317: 1141. https://pubmed.ncbi.nlm.nih.gov/28324092

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Sanda, M.G., et al. Clinically Localized Prostate Cancer: AUA/ASTRO/SUO Guideline. Part I: Risk Stratification, Shared Decision Making, and Care Options. J Urol, 2018. 99: 683. https://pubmed.ncbi.nlm.nih.gov/29203269 Makarov, D.V., et al. AUA white paper on implementation of shared decision making into urological practice. Urol Pract, 2016. 3: 355. https://www.sciencedirect.com/science/article/abs/pii/S2352077915002733 Stiggelbout, A.M., et al. Shared decision making: Concepts, evidence, and practice. Patient Educ Couns, 2015. 98: 1172. https://pubmed.ncbi.nlm.nih.gov/26215573 Violette, P.D., et al. Decision aids for localized prostate cancer treatment choice: Systematic review and meta-analysis. CA Cancer J Clin, 2015. 65: 239. https://pubmed.ncbi.nlm.nih.gov/25772796 Ramsey, S.D., et al. Unanticipated and underappreciated outcomes during management of local stage prostate cancer: a prospective survey. J Urol, 2010. 184: 120. https://pubmed.ncbi.nlm.nih.gov/20478590 Connolly, T., et al. Regret in decision making. Curr Direct Psycho Sci, 2002. 11: 212. https://pubmed.ncbi.nlm.nih.gov/16045415 Maguire, R., et al. Expecting the worst? The relationship between retrospective and prospective appraisals of illness on quality of life in prostate cancer survivors. Psychooncology, 2018. 27: 1237. https://pubmed.ncbi.nlm.nih.gov/29430755 Schroeck, F.R., et al. Satisfaction and regret after open retropubic or robot-assisted laparoscopic radical prostatectomy. Eur Urol, 2008. 54: 785. https://pubmed.ncbi.nlm.nih.gov/18585849 Steentjes, L., et al. Factors associated with current and severe physical side-effects after prostate cancer treatment: What men report. Eur J Cancer Care (Engl), 2018. 27. https://pubmed.ncbi.nlm.nih.gov/27726215 Orom, H., et al. What Is a “Good” Treatment Decision? Decisional Control, Knowledge, Treatment Decision Making, and Quality of Life in Men with Clinically Localized Prostate Cancer. Med Decis Making, 2016. 36: 714. https://pubmed.ncbi.nlm.nih.gov/26957566 Davison, B.J., et al. Quality of life, sexual function and decisional regret at 1 year after surgical treatment for localized prostate cancer. BJU Int, 2007. 100: 780. https://pubmed.ncbi.nlm.nih.gov/17578466 Martínez-González, N.A., et al. Shared decision making for men facing prostate cancer treatment: a systematic review of randomized controlled trials. Patient Prefer Adherence, 2019. 13: 1153. https://pubmed.ncbi.nlm.nih.gov/31413545 Menichetti, J., et al. Quality of life in active surveillance and the associations with decision-making-a literature review. Transl Androl Urol, 2018. 7: 160. https://pubmed.ncbi.nlm.nih.gov/29594030 Ivlev, I., et al. Prostate Cancer Screening Patient Decision Aids: A Systematic Review and Metaanalysis. Am J Prev Med, 2018. 55: 896. https://pubmed.ncbi.nlm.nih.gov/30337235 Kinsella, N., et al. A Single Educational Seminar Increases Confidence and Decreases Dropout from Active Surveillance by 5 Years After Diagnosis of Prostate Cancer. Eur Urol Oncol, 2019. 2: 464. https://pubmed.ncbi.nlm.nih.gov/31277784 Hoffman, R.M., et al. Selecting Active Surveillance: Decision Making Factors for Men with a LowRisk Prostate Cancer. Med Decis Making, 2019. 39: 962. https://pubmed.ncbi.nlm.nih.gov/31631745 Berry, D.L., et al. Decision Support with the Personal Patient Profile-Prostate: A Multicenter Randomized Trial. J Urol, 2018. 199: 89. https://pubmed.ncbi.nlm.nih.gov/28754540 Campagna, J.P., et al. Prostate Cancer Survival Estimates by the General Public Using Unrestricted Internet Searches and Online Nomograms. Eur Urol Focus, 2020. 6: 959. https://pubmed.ncbi.nlm.nih.gov/30723050 de Freitas, H.M., et al. Patient Preferences for Metastatic Hormone-Sensitive Prostate Cancer Treatments: A Discrete Choice Experiment Among Men in Three European Countries. Adv Ther, 2019. 36: 318. https://pubmed.ncbi.nlm.nih.gov/30617763

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10. CONFLICT OF INTEREST All members of the EAU-EANM-ESTRO-ESUR-SIOG Prostate Cancer Guidelines Panel have provided disclosure statements of all relationships that they have that might be perceived as a potential source of a conflict of interest. This information is publicly accessible through the European Association of Urology website: https://uroweb.org/guideline/prostate-cancer/. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organization and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

11. CITATION INFORMATION The format in which to cite the EAU Guidelines will vary depending on the style guide of the journal in which the citation appears. Accordingly, the number of authors or whether, for instance, to include the publisher, location, or an ISBN number may vary. The compilation of the complete Guidelines should be referenced as: EAU Guidelines. Edn. presented at the EAU Annual Congress Milan 2021. ISBN 978-94-92671-13-4. If a publisher and/or location is required, include: EAU Guidelines Office, Arnhem, The Netherlands. http://uroweb.org/guidelines/compilations-of-all-guidelines/ References to individual guidelines should be structured in the following way: Contributors’ names. Title of resource. Publication type. ISBN. Publisher and publisher location, year.

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EAU Guidelines on

Renal Transplantation A. Breda (Chair), K. Budde, A. Figueiredo, E. Lledó García, J. Olsburgh (Vice-chair), H. Regele Guidelines Associates: R. Boissier, V. Hevia, O. Rodríguez Faba, R.H. Zakri

© European Association of Urology 2021

TABLE OF CONTENTS

PAGE

Inhoud 1. INTRODUCTION 1.1 Aim and objectives 1.2 Panel Composition 1.3 Available publications 1.4 Publication history

4 4 4 4 4

2.

4 4 5

METHODS 2.1 Introduction 2.2 Review and future goals

3. THE GUIDELINE 5 3.1 Organ retrieval and transplantation surgery 5 3.1.1 Living-donor nephrectomy 5 3.1.2 Organ preservation 6 3.1.2.1 Kidney storage solutions and cold storage 6 3.1.2.2 Duration of organ preservation 7 3.1.2.3 Methods of kidney preservation: static and dynamic preservation 7 3.1.3 Donor Kidney biopsies 9 3.1.3.1 Procurement Biopsies 9 3.1.3.1.1 Background and prognostic value 9 3.1.3.2 Type and size of biopsy 10 3.1.3.3 Summary of evidence and recommendations 10 3.1.3.4 Implantation biopsies 10 3.1.4 Living and deceased donor implantation surgery 11 3.1.4.1 Anaesthetic and peri-operative aspects 11 3.1.4.2 Immediate pre-op haemodialysis 11 3.1.4.3 Operating on patients taking anti-platelet and anti-coagulation agents 11 3.1.4.4 What measures should be taken to prevent venous thrombosis including deep vein thrombosis during and after renal transplant? 11 3.1.4.5 Is there a role for peri-operative antibiotics in renal transplantation? 12 3.1.4.6 Is there a role for specific fluid regimes during renal transplantation and central venous pressure measurement in kidney transplant recipients? 12 3.1.4.7 Is there a role for dopaminergic drugs, furosemide or mannitol in renal transplantation? 13 3.1.5 Surgical approaches for first, second, third and further transplants 13 3.1.5.1 Single kidney transplant - living and deceased donors 14 3.1.5.2 Robot-assisted kidney transplant surgery 16 3.1.5.3 Dual kidney transplants 16 3.1.5.4 Ureteric implantation in normal urinary tract 16 3.1.5.5 Transplantation/ureteric implantation in abnormal urogenital tract 18 3.1.6 Donor complications 18 3.1.6.1 Long-term complications 18 3.1.7 Recipient complications 19 3.1.7.1 General complications 19 3.1.7.2 Haemorrhage 19 3.1.7.3 Arterial thrombosis 19 3.1.7.4 Venous thrombosis 20 3.1.7.5 Transplant renal artery stenosis. 20 3.1.7.6 Arteriovenous fistulae and pseudo-aneurysms after renal biopsy 21 3.1.7.7 Lymphocele 21 3.1.7.8 Urinary leak 21 3.1.7.9 Ureteral stenosis 22 3.1.7.10 Haematuria 22 3.1.7.11 Reflux and acute pyelonephritis 22 3.1.7.12 Kidney stones 23 3.1.7.13 Wound infection 23

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3.1.7.14 Incisional hernia 3.1.8 Urological malignancy and renal transplantation 3.1.8.1 Malignancy prior to renal transplantation 3.1.8.1.1 In the recipient 3.1.8.1.2 In the potential donor kidney 3.1.8.2 Malignancy after renal transplantation 3.1.9 Matching of donors and recipients 3.1.10 Immunosuppression after kidney transplantation 3.1.10.1 Calcineurin inhibitors 3.1.10.2 Mycophenolates 3.1.10.3 Azathioprine 3.1.10.4 Steroids 3.1.10.5 Inhibitors of the mammalian target of rapamycin 3.1.10.6 Induction with Interleukin-2 receptor antibodies 3.1.10.7 T-cell depleting induction therapy 3.1.10.8 Belatacept 3.1.11 Immunological complications 3.1.11.1 Hyper-acute rejection 3.1.11.2 Treatment of T-cell mediated acute rejection 3.1.11.3 Treatment of antibody mediated rejection (ABMR) 3.1.12 Follow-up after transplantation 3.1.12.1 Chronic allograft dysfunction/interstitial fibrosis and tubular atrophy

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CITATION INFORMATION

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INTRODUCTION

1.1

Aim and objectives

The European Association of Urology (EAU) Renal Transplantation Guidelines aim to provide a comprehensive overview of the medical and technical aspects relating to renal transplantation. It must be emphasised that clinical guidelines present the best evidence available to the experts but following guideline recommendations will not necessarily result in the best outcome. Guidelines can never replace clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions - also taking personal values and preferences/individual circumstances of patients into account. Guidelines are not mandates and do not purport to be a legal standard of care.

1.2

Panel Composition

The EAU Renal Transplantation Guidelines panel consists of an international multidisciplinary group of urological surgeons, a nephrologist and a pathologist. All experts involved in the production of this document have submitted potential conflict of interest statements which can be viewed on the EAU website: http://www.uroweb.org/guideline/renal-transplantation/.

1.3

Available publications

A quick reference document, the Pocket Guidelines, is available in print and as an app for iOS and Android devices. These are abridged versions which may require consultation together with the full text version. All are available through the EAU website: http://www.uroweb.org/guideline/renal-transplantation/.

1.4

Publication history

The EAU published the first Renal Transplantation Guidelines in 2003 with updates in 2004 and 2009. A comprehensive update of the 2009 document was published in 2017. This document is a full update of the 2017 Renal Transplantation Guidelines.

2.

METHODS

2.1

Introduction

For the 2021 Renal Transplantation Guidelines, new and relevant evidence was identified, collated and appraised through a structured assessment of the literature. Broad and comprehensive literature searches, covering the Renal Transplantation Guidelines were performed, covering a time frame between May 31st 2018 and 1st April 2020. A total of 1,202 unique records were identified, retrieved and screened for relevance. Databases searched included Medline, EMBASE, and the Cochrane Libraries. Detailed search strategies are available online: http://www.uroweb.org/guideline/renal-transplantation/. For each recommendation within the guidelines there is an accompanying online strength rating form, the bases of which is a modified GRADE methodology [1, 2]. Each strength rating form addresses a number of key elements namely: 1. the overall quality of the evidence which exists for the recommendation, references used in this text are graded according to a classification system modified from the Oxford Centre for Evidence-Based Medicine Levels of Evidence [3]; 2. the magnitude of the effect (individual or combined effects); 3. the certainty of the results (precision, consistency, heterogeneity and other statistical or study related factors); 4. the balance between desirable and undesirable outcomes; 5. the impact of patient values and preferences on the intervention; 6. the certainty of those patient values and preferences. These key elements are the basis which panels use to define the strength rating of each recommendation. The strength of each recommendation is represented by the words ‘strong’ or ‘weak’ [4]. The strength of each recommendation is determined by the balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including certainty of estimates), and nature and variability of patient values and preferences.

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Additional information can be found in the general Methodology section of this print, and online at the EAU website; http://www.uroweb.org/guideline/. A list of associations endorsing the EAU Guidelines can also be viewed online at the above address.

2.2

Review and future goals

This document was subject to independent peer review prior to publication in 2017. Publications ensuing from systematic reviews have all been peer reviewed. The results of ongoing systematic reviews will be included in the 2022 update of the Renal Transplantation Guidelines. Ongoing systematic reviews include: 1. What is the best treatment for symptomatic obstructive benign prostatic enlargement in renal transplantation patients [5]? 2. For patients with kidney graft stones, does surgical treatment provide better stone free rates than external shock wave lithotripsy [6]?

3.

THE GUIDELINE

3.1

Organ retrieval and transplantation surgery

3.1.1 Living-donor nephrectomy The endoscopic (laparoscopic) approach is the preferred technique for living-donor nephrectomy in established kidney transplant programmes [7]. Nevertheless, open surgery, preferably by a mini-incision approach, can still be considered a valid option, despite increased pain in the post-operative period [8]. Endoscopic living-donor nephrectomy (ELDN) includes: • Pure or hand-assisted transperitoneal laparoscopy; • Pure or hand-assisted retroperitoneal approach; • Laparo-Endoscopic Single Site Surgery (LESS); • Natural Orifice Transluminal Endoscopic Surgery-assisted (NOTES); • Laparo-Endoscopic Single Site Surgery and robotic-assisted transperitoneal or retroperitoneal approach. There is strong evidence in support of laparoscopic living-donor nephrectomy (LLDN), including several systematic reviews and meta-analysis, which have compared its safety and efficacy to open donor nephrectomy. Laparoscopic living-donor nephrectomy is associated with similar rates of graft function and rejection, urological complications and patient and graft survival. However, measures related to analgesic requirements, pain, hospital stay, and time to return to work are significantly better for laparoscopic procedures [9-12]. Standard LLDN is usually done through 5 and 12 mm ports, but has also been done with 3 or 3.5 mm ports [13]. According to a recent meta-analysis, hand-assisted LLDN is associated with shorter operative time and warm ischaemia, but equivalent safety and overall results [14]. Laparoscopic living-donor nephrectomy can also be performed with robotic assistance, with equivalent results according to a systematic review [15]. However, the numbers are still low and recent studies, including a meta-analysis, have reported higher complication rates for this approach [16, 17]. Laparo-endoscopic single site surgery nephrectomy allows the surgeon to work through a single incision (usually the umbilicus) with a multi-entry port. The same or a separate incision is then used for kidney withdrawal. Several retrospective and at least three prospective randomised trials demonstrated equivalent safety and results, with a trend towards less pain and better cosmetic results [18, 19]. However, LESS is considered a more technically demanding procedure when compared with classic LLDN and its role is yet to be defined. Natural orifice transluminal endoscopic surgery-assisted transvaginal nephrectomy avoids the abdominal incision needed for kidney extraction, aimed at minimising scaring and pain. Initial reports suggest that this approach is safe, however experience with this technique is still highly limited [20]. Right LLDN has been considered more difficult, yielding inferior results. However, both left and right LLDN can be performed with equivalent safety and efficacy according to large retrospective studies, systematic reviews and meta-analysis [21, 22].

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Laparoscopic living-donor nephrectomy has brought attention to potential failures of different devices such as, endoscopic staplers and locking and non-locking clips, used to secure the renal hilum [21]. There is no scientific evidence that one device is safer than another for securing the renal artery [23-25]. However, the U.S. Food and Drug Administration (FDA) and the manufacturers of locking clips have issued a contraindication against their use in securing the artery during LLDN. Summary of evidence LE Laparoscopic living-donor nephrectomy is associated with similar rates of graft function and rejection, 1a urological complications and patient and graft survival to open nephrectomy. Measures related to analgesic requirements, pain, hospital stay, and time to return to work are 1a significantly better for laparoscopic procedures.

Recommendations Offer pure or hand-assisted laparoscopic/retroperitoneoscopic surgery as the preferential technique for living-donor nephrectomy. Perform open living-donor nephrectomy in centres where endoscopic techniques are not implemented. Perform laparo-endoscopic single site surgery, robotic and natural orifice transluminal endoscopic surgery-assisted living-donor nephrectomy in highly-specialised centres only.

Strength rating Strong Strong Strong

3.1.2 Organ preservation In kidneys donated after cardiac death (DCD) evidence suggests that warm ischemia contributes to worse graft outcome. Donor haemodynamic parameters (systolic blood pressure, oxygen saturation and shock index: heart rate divided by systolic blood pressure) may be predictors of delayed graft function (DGF) and graft failure; however, further studies are required to validate this [26]. The duration of asystolic warm ischaemia during procurement in DCD donors is associated with increased risk of graft failure. Overall five year graft failure (including primary graft non-function) was associated with longer asystolic warm ischaemia times [27]. Extraction time (beginning with aortic cross-clamp and ending with placement of the kidneys on ice), is an important factor for DGF. Incidents of DGF were 27.8% and 60% at up to 60 minutes and 120 minutes extraction time, respectively [28]. A retrospective study of 64,024 living donor kidney transplants found that cold ischaemia time (CIT), human leukocyte antigen (HLA) mismatch, donor age, panel reactive antibody, recipient diabetes, donor and recipient body mass index (BMI), recipient race and gender, right nephrectomy, open nephrectomy, dialysis status, ABO incompatibility, and previous transplants were independent predictors of DGF in living donor kidney transplants [29]. Five-year graft survival among living donor kidney transplant recipients with DGF was significantly lower than in those without DGF. Delayed graft function increased the risk of graft failure by more than two-fold [29]. 3.1.2.1 Kidney storage solutions and cold storage There are two main sources for kidney graft injury: ischaemia (warm and cold), and reperfusion injury. The aims of modern kidney storage solutions include: control of cell-swelling during hypothermic ischaemia; maintenance of intra- and extra-cellular electrolyte gradient during ischaemia; buffering of acidosis; provision of energy reserve; and minimisation of oxidative reperfusion injury. There is no agreement on which of the mechanisms is most important for post-ischaemic renal graft function [30]. No storage solution seems to combine all mechanisms. Previously, Euro-Collins was widely used, but is no longer recommended. Presently, University of Wisconsin (UW), and histidine-tryptophan-ketoglutarate (HTK) solution are equally effective and are standard for multi-organ or single kidney harvesting procedures. The characteristics of HTK are its low viscosity, low potassium concentration and low cost. University of Wisconsin solution has been the standard static cold preservation solution for the procurement of liver, kidney, pancreas, and intestine [31]. University of Wisconsin, HTK, and Celsior solutions have provided similar allograft outcomes in most clinical trials; however, some differences have become apparent in recent studies and registry reports [32, 33]. Marshall’s hypertonic citrate solution (MHCS) is also suitable for use in the preservation of human kidneys before transplantation [34]. In experimental studies of kidney preservation, HTK and UW retained a greater capacity to preserve endothelial structure and pH buffering function during warm ischaemia in comparison to MHCS and Celsior, especially in uncontrolled DCD donors [35]. In the absence of a cost-utility analysis, the results of the meta-analysis from the randomised controlled trials (RCTs) comparing UW with Celsior and MHSC in standard cadaver donors, indicate that these cold storage solutions are equivalent [36].

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For living donors, in whom immediate kidney transplantation is planned, perfusion with crystalloid solution is sufficient. Kidneys coming from DCD donors, especially those uncontrolled, are high-risk marginal organs due to prolonged warm ischaemia periods, and require specific measures in order to diminish the rate of nonfunction or DGF. More than 60% of kidney grafts currently come from Expanded Criteria Donors (ECD) (any donor aged > 65 years and/or donor aged > 55 years with any of the following: acute renal dysfunction, stroke or arterial hypertension) [37]. Summary of evidence University of Wisconsin and HTK solution are equally effective and are standard for multi-organ or single kidney harvesting procedures. A meta-analysis of RCTs indicated that UW and Celsior solution are equivalent in standard cadaver donors. Recommendations Use either University of Wisconsin or histidine tryptophane ketoglutarate preservation solutions for cold storage. Use Celsior or Marshall’s solution for cold storage if University of Wisconsin or histidine tryptophane ketoglutarate solutions are not available.

LE 1b 1a

Strength rating Strong Strong

3.1.2.2 Duration of organ preservation Cold ischaemia time should be as short as possible. Kidneys from ECDs after brain death (DBD) and DCD donors are more sensitive to ischaemia than standard criteria donors. Kidneys from DBD donors should ideally be transplanted within a 18 to 21 hour time period; there is no significant influence on graft survival within a 18 hour CIT [36, 38, 39]. Kidneys from DCD donors should ideally be transplanted within 12 hours [40], whilst kidneys from ECDs should ideally be transplanted within 12 to 15 hours [41, 42]. 3.1.2.3 Methods of kidney preservation: static and dynamic preservation Whichever method is used, cold storage is critical. The use of cold preservation as a therapeutic window to deliver pharmacological or gene therapy treatments could, from an investigational point of view, improve both short- and long-term graft outcomes [43]. Cooling reduces the metabolic rate of biological tissue minimising continuous cellular processes that lead to depletion of ATP and accumulation of metabolic products. Reperfusion with oxygenated blood invokes ischaemia-reperfusion injury. Hypothermic perfusion does not enable normal cellular metabolic function or prevent depletion of energy stores [44]; however, it prevents the deleterious effects of simple cooling, especially in the setting of prolonged warm-ischaemic time in uncontrolled DCD donors. Two meta-analyses suggest that hypothermic machine perfusion (HMP) reduces DGF compared with static cold storage [45, 46]. Outcomes for primary non-function (PNF) are less clear, but one meta-analysis limited to high quality studies suggests a reduction in PNF rates with HMP [46]. A Cochrane systematic review and meta-analysis showed that HMP reduced the risk of DGF when compared to static cold storage (CS) for kidneys from both DCD and DBD donors [47]. The increased demand for organs has led to the increased use of “higher risk” kidney grafts. Kidneys from DCD donors or grafts coming from ECDs are more susceptible to preservation injury and have a higher risk of unfavourable outcomes [48, 49]. Dynamic, instead of static, preservation could allow for organ optimisation, offering a platform for viability assessment, active organ repair and resuscitation. Ex situ machine perfusion and in situ regional perfusion in the donor are emerging as potential tools to preserve vulnerable grafts. Preclinical findings have driven clinical organ preservation research that investigates dynamic preservation, in various modes (continuous, pre-implantation) and temperatures (hypo-, sub-, or normothermic) [44]. There are several methods of kidney preservation including: • Initial flushing with cold preservation solution followed by ice storage. However, the limitations of static CS in preserving marginal organs such as ECD kidneys has led to the increased use of dynamic methods. • Current dynamic preservation strategies entering clinical practice and the different modalities of their use are: HMP, hypothermic regional perfusion, normothermic machine perfusion, normothermic regional perfusion, sub-normothermic machine perfusion and sub-normothermic regional perfusion [44]. • Continuous pulsatile HMP seems to be a good preservation method for marginal organs, either initially or after a period of simple CS (shipping of suboptimal kidneys) [50].

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•

•

Some evidence shows that hypothermic dynamic preservation should be controlled by pressure and not flow, using low pressures to avoid pressure-related injury. The perfusion solutions used are specific, and are qualitatively different to CS solutions [33]. Nonoxygenated HMP of the kidney at low perfusion pressures (20-30 mmHg) has been shown to reduce DGF [45]. The largest RCT comparing simple CS with HMP of deceased donor kidneys showed an overall reduced risk of DGF and a survival benefit, most pronounced in ECD kidneys [51]. Hypothermic machine perfusion of kidneys from type III DCD donors decreased DGF with no impact on graft survival [48]. Hypothermic machine-perfusion reduces the risk of DGF in standard criteria DBD donor kidneys regardless of CIT [52]. Increased vascular resistance and high perfusate injury marker concentrations are risk factors for DGF; however, they do not justify discarding the kidney. The flow perfusion value seems to be an indicator of graft viability in uncontrolled DCD donors, particularly donors with a high creatinine level [53]. However, research is required to identify a strong and reliable measure for predicting kidney viability from machine perfusion [36]. Perfusion parameters (renal flow and renal vascular resistance) have low predictive values and should not be used as the sole criterion to assess viability of kidney grafts [54]. The effect of oxygenated HMP was investigated in an RCT initiated by the Consortium on Organ Preservation in Europe on type III DCD kidneys and ECD kidneys [44]. Graft loss was significantly lower after oxygenated HMP compared to HMP [55]. No significant differences between the two groups were shown for DGF, PNF and patient death. No difference in eGFR at one year was observed between HMPO vs. HMP; however, sensitivity analysis, accounting for all-cause graft failure, showed a higher eGFR in oxygenated HMP [55]. A short period of normothermic machine perfusion (NMP) immediately prior to implantation has been shown to improve kidney graft function, replenish ATP and reduce injury in experimental models [56, 57]. A retrospective study of normothermic regional perfusion (NRP) in uncontrolled DCD donors concluded that NRP appears to decrease graft failure when used as a preconditioning technique with subsequent HMP preservation in these donors [58]. Active research is being developed on preservation of prolonged warm-ischaemically damaged human kidneys (types I and II DCD) by in situ normothermic extracorporal hemoperfusion with oxygenation and leukocyte depletion before procurement [59]. Oxygen carriage is achieved by using blood depleted of leukocytes. Potential advantages of this preservation technique are reduction in ischaemia-reperfusion injury as well as the possibility of assessing organ viability. Currently there is one registered ongoing RCT on pre-implantation NMP using an oxygenated, sanguineous normothermic perfusion solution (http://www.isrctn.com/ISRCTN15821205). However, kidney function can be evaluated during NMP by assessing macroscopic appearance of blood perfusion, renal blood flow and urine output [60]. Continuous subnormothermic machine perfusion and controlled oxygenated rewarming has demonstrated improved creatinine clearance and preservation of structural integrity compared with continuous oxygenated HMP in a research setting [61].

Summary of evidence A meta-analysis of RCTs comparing CS with HMP of deceased donor kidneys showed a reduced risk of DGF for HMP. Hypothermic dynamic preservation should be controlled by pressure and not flow, using low pressures to avoid pressure-related injury. Perfusion parameters (renal flow and renal vascular resistance) have low predictive values and should not be used as the sole criterion to assess viability of kidney grafts.

Recommendations Minimise ischaemia times. Use hypothermic machine-perfusion (where available) in deceased donor kidneys to reduce delayed graft function. Hypothermic machine-perfusion may be used in standard criteria deceased donor kidneys. Use low pressure values in hypothermic machine perfusion preservation. Hypothermic machine-perfusion must be continuous and controlled by pressure and not flow. Do not discard grafts based only on increased vascular resistance and high perfusate injury marker concentrations during hypothermic machine perfusion preservation.

8

LE 1a 2a 2b

Strength rating Strong Strong Strong Strong Strong Weak

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3.1.3 Donor Kidney biopsies Donor kidney biopsies can serve different purposes including: • histological assessment of organ quality prior to transplantation (often referred to as procurement or harvest biopsies); • histological analysis of focal lesions, especially if there is a suspicion of neoplasia; • detection of donor derived lesions as reference for subsequent post-transplant biopsies (often referred to as baseline, zero-time or implantation biopsies). 3.1.3.1 Procurement Biopsies 3.1.3.1.1 Background and prognostic value Procurement biopsies are used for the detection of tissue injury to aid the decision of whether or not a deceased donor kidney is suitable for transplantation. These biopsies are most commonly performed in donors with clinical suspicion of chronic kidney injury (ECDs) [62]. Kidney discard in Europe is rarely based on histology findings, as procurement biopsies are not regularly performed for graft allocation in the Eurotransplant region [62]. However, since biopsy findings are the most frequent cause for discarding donor organs in the United States [63-65], their prognostic value has been analysed in numerous studies. A recently published systematic review of studies on donor kidney biopsies revealed a lack of prospective studies and marked heterogeneity regarding the type of lesions being assessed, their scoring, the definitions of post-transplant outcomes and the statistical methods employed [66]. Therefore, the published evidence suggests that the use of procurement biopsies for deciding on suitability for transplantation of donor kidneys may have some important limitations including the following [62, 66, 67]: There is no consistent association between histological lesions observed in donor kidney biopsies and post-transplant outcomes. The concept of procurement biopsies in elderly donors was introduced by a study from Gaber et al., in 1995. This study observed significantly worse outcomes in recipients of kidneys with > 20% globally sclerotic glomeruli [68]. However, subsequent studies yielded highly variable results and it cannot be concluded that glomerulosclerosis is independently associated with graft outcomes [66]. A similar variability was also observed for other potentially relevant lesions like arterial injury, interstitial fibrosis and tubular atrophy with each showing predictive value in some studies, but not in others [66]. •

• There is no agreement on prognostically relevant lesions and how they should be scored. Specific grading systems for donor kidney biopsies have not yet been developed. Lesion scoring in pretransplant biopsies is mostly based on the Banff consensus for post-transplant renal allograft pathology, which is supported by the 2007 Banff Conference report [69]. Many attempts have been made to use composite semi-quantitative scoring systems to express the global extent of tissue injury in donor kidney biopsies. These scoring systems are mostly based on simple addition of the Banff scores for individual lesions, most commonly glomerulosclerosis, arteriolar hyalinosis, arterial intimal fibrosis, interstitial fibrosis and tubular atrophy and rarely include clinical parameters like donor age [70], serum creatinine values and donor hypertension [71]. A limited number of histological scoring systems are based on modelling analysis [70-74]. Only the Maryland Aggregate Pathology Index (MAPI) [74] scoring system and the Leuven donor risk score [70], use graft failure as their endpoint and have been independently validated in a second cohort. Other studies used surrogate clinical endpoints like DGF [72] and estimated glomerular filtration rate (eGFR) at three months [73] to calculate histological models. In addition, these models were not validated in independent cohorts. The variation in how the components are weighted to achieve the composite score and the different endpoints used may explain the conflicting conclusions in the literature [62, 66, 67]. Due to the time constraints of organ allocation procurement biopsies are mostly read on frozen sections by on-call pathologists, which might affect the diagnostic reliability of reported findings. This may have substantial impact on the diagnostic reliability of the procedure since frozen sections are prone to morphological artefacts that can impair the detection and scoring of potentially important lesions such as arteriolar hyalinosis and interstitial fibrosis [75, 76]. There is strong evidence that dedicated renal pathologists should examine formalin-fixed paraffin-embedded core-needle biopsies. Paraffin histology employing special stains is technically superior to frozen sections since morphological details are better preserved on paraffin sections than on frozen sections and potentially confounding artefacts can be avoided. Rapid processing of tissue for paraffin histology is technically feasible, but the respective protocols are not universally implemented and are not available on a 24/7 basis in most departments. Another source of variability is the professional experience of the pathologist in charge. Procurement biopsies are commonly read by the on-call general •

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pathologist who frequently has no specific training in renal pathology. A recent study specifically addressing this issue found that the on-call pathologists tended to overestimate chronic injury in biopsies [77]. 3.1.3.2 Type and size of biopsy Many transplant centres obtain wedge biopsies of donor kidneys rather than needle biopsies due to the presumed higher risk of bleeding complications with the latter. Wedge biopsies sample the cortex superficially whereas needle biopsies reach deeper aspects of the cortex. Needle biopsies also allow sampling from different areas of the kidney. Submit 14 or 16 G needle biopsies as obtaining adequate biopsies with 18 G needles requires multiple cores [78]. Several studies comparing wedge with needle biopsies concluded that needle biopsies perform much better in the evaluation of vascular lesions because interlobular arteries are rarely sampled in wedge biopsies. Both methods were comparable for glomerular or tubulointerstitial lesions [79-82]. It was also demonstrated that glomerulosclerosis is significantly more pronounced in the subcapsular zone compared with deeper areas of the cortex [83]. The problem of insufficient sampling of arteries and over representation of (subcapsular) glomerular scars in wedge biopsies, can only be avoided if particular attention is paid to the correct performance of the biopsy, with a minimal depth of 5 mm [84]. The predictive value of glomerulosclerosis increases significantly with higher numbers of glomeruli in the wedge biopsy, with ideally at least 25 glomeruli required for evaluation [81]. There is limited evidence regarding complication rates in preimplantation biopsies. Use of a skin punch biopsy device might be an attractive alternative. Skin punch biopsies measure 3 mm in diameter. They have a shorter length than needle biopsies therefore avoiding injury to large calibre arteries at the corticomedullary junction whilst still sampling tissue from deeper areas of the cortex [85]. 3.1.3.3

Summary of evidence and recommendations

Summary of evidence Individual histologic lesions like glomerulosclerosis, arterial luminal narrowing or tubulointerstitial injury observed in donor kidney biopsies have limited prognostic value for long-term allograft survival. Composite histological scoring systems provide a more comprehensive measure of overall organ damage. However, published scoring systems still lack independent validation and robust thresholds. Size of the biopsy is of critical importance for its diagnostic value. An adequate biopsy reaches beyond the immediate subcapsular area (≥ 5 mm) and contains ≥ 25 glomeruli and ≥ one artery. Needle biopsies, wedge biopsies or specimens obtained with a skin punch biopsy device will result in equally adequate biopsies if sampling is properly performed. Obtaining adequate biopsies with 18 G needles is difficult and requires multiple cores.

Recommendations Do not base decisions on the acceptance of a donor organ on histological findings alone, since this might lead to an unnecessary high rate of discarded grafts. Interpret histology in context with clinical parameters of donor and recipient including perfusion parameters where available. Use paraffin histology for histomorphology as it is superior to frozen sections; however, its diagnostic value has to be balanced against a potential delay of transplantation. Procurement biopsies should be read by a renal pathologist or a general pathologist with specific training in kidney pathology.

LE 3 3 3

Strength rating Strong

Strong Strong

3.1.3.4 Implantation biopsies Implantation biopsies are used to provide baseline information on donor kidney injury for comparison with subsequent post-transplant kidney biopsies. Baseline biopsies can be essential for clear distinction between pre-existing damage and acquired lesions. They are particularly valuable in cases of thrombotic microangiopathy, arteriolar hyalinosis or acute tubular injury. In contrast to procurement biopsies that are obtained at the time of organ harvesting, implantation biopsies are usually taken before implantation in order to cover potential effects of CIT. Their diagnostic contribution has not been formally quantified in the literature which might be due to the difficulties of measuring the value of implantation biopsies for improving diagnoses. Despite the lack of formal studies investigating their value it seems very reasonable to perform implantation biopsies in deceased donor kidneys.

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3.1.4 Living and deceased donor implantation surgery 3.1.4.1 Anaesthetic and peri-operative aspects Good communication between nephrologists, anaesthetists and surgeons is required for optimal anaesthetic and peri-operative care of the renal transplant patient. Anaesthetic care of the living kidney donor [86] and renal transplant recipient [87] have been reviewed and recent guidelines from the European Renal AssociationEuropean Dialysis and Transplantation Association (ERA-EDTA) [88] are cross referenced. 3.1.4.2 Immediate pre-op haemodialysis Routine use of haemodialysis immediately prior to renal transplantation is not indicated [88]. Hyperkalaemia is the most common indication for haemodialysis pre-operatively. The risks of haemodialysis compared with medical therapy must be considered along with the risks of intra-operative fluid overload, electrolyte and acidbase disturbances, particularly where a deceased donor kidney is transplanted with a significant risk of DGF. Pre-operative haemodialysis may initiate a pro-inflammatory state, delay surgery, increase the CIT and increase the risk of DGF [89]. Summary of evidence Pre-operative haemodialysis has the potential to delay transplantation, increase CIT and increase the risk of DGF.

Recommendation Use dialysis or conservative measures to manage fluid and electrolyte imbalance prior to transplant surgery taking into consideration the likelihood of immediate graft function.

LE 2

Strength rating Weak

3.1.4.3 Operating on patients taking anti-platelet and anti-coagulation agents Many patients active on the transplant waiting list have vascular disease and/or a pro-thrombotic condition that should be risk-assessed prior to transplantation. Dual anti-platelet therapy is commonly given to patients with coronary artery stents for six to twelve months; peri-operative management plans for these patients should be discussed with a cardiologist so that the risks of withdrawal of the anti-platelet agent can be fully considered. Options for reversal of anti-coagulation and post-operative anti-coagulation should be discussed with a haematologist prior to patient listing. Some patients will be active on a transplant waiting list whilst continuing to take anti-platelet and/or anticoagulation agents. The indication for anti-platelet or anti-coagulation agents should be clearly documented for each individual. Potential increased risk of peri-operative bleeding needs to be weighed against potential harm from arterial or venous thrombosis. In accordance with the American College of Chest Physicians and the European Society of Cardiology guidelines [90, 91], the literature suggests that continuing anti-platelet therapy with aspirin, ticlopidine or clopidogrel does not confer a significantly greater risk of peri/post-operative complications [92], however, the number of patients studied was low. If needed, the effect of anti-platelet agents can be reduced with intra-operative platelet infusions. Summary of evidence A retrospective single-centre case-control study in patients undergoing kidney transplantation concluded that continuing anti-platelet therapy with aspirin, ticlopidine or clopidogrel does not confer a significantly greater risk of peri/post-operative complications.

Recommendations Consider continuing anti-platelet therapy in patients on the transplant waiting list. Discuss patients who take anti-platelet and anti-coagulation agents prior to transplant surgery with relevant cardiologist/haematologist/nephrologist.

LE 3

Strength rating Weak Weak

3.1.4.4

What measures should be taken to prevent venous thrombosis including deep vein thrombosis during and after renal transplant? Peri-operative administration of short-acting anti-coagulation agents reduces peri-operative risk of venous thrombosis (including in ileo-femoral and renal veins); however, due to associated increased blood loss administration requires knowledge of individual patient risk factors. None of the current major thrombosis prevention guidelines directly address thromboprophylaxis in the renal transplant peri-operative period. A small

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RCT [93] showed no difference in early post-operative graft loss or thromboembolic complications with or without prophylactic anti-coagulation. Those administered prophylactic anti-coagulation had significantly lower haemoglobin whilst those administered prophylactic unfractionated heparin had prolonged lymph drainage. Based on this study, routine pharmacological prophylaxis is not recommended in low-risk living donor recipients. Mechanical measures to decrease ileo-femoral deep vein thrombosis (DVT) can be used where there is no contraindication due to peripheral vascular disease particularly where there are concerns about bleeding risks with pharmacological prophylaxis. Summary of evidence A small RCT (n=75) showed no difference in early post-operative graft loss or thromboembolic complications with or without prophylactic anti-coagulation.

Recommendation Do not routinely give post-operative prophylactic unfractionated or low-molecular-weight heparin to low-risk living donor transplant recipients.

LE 1b

Strength rating Weak

3.1.4.5 Is there a role for peri-operative antibiotics in renal transplantation? Prophylactic peri-operative antibiotics are generally used in renal transplant surgery but the optimal antibiotic regimen is not known and increasing antibiotic resistance may hamper their effectiveness in this setting. A multicentre, prospective RCT showed no difference at one month in surgical site, bacterial, fungal or viral infection between those receiving a single dose broad spectrum antibiotic at induction of anaesthesia compared to those receiving antibiotic 12 hourly for 3-5 days [94]. A retrospective comparison of peri-operative intravenous cefazolin prophylaxis compared to no antibiotic showed no difference in infectious complications (surgical site, urinary tract, bacteraemia or central catheter-related infection) in the first month after renal transplantation [95]. Summary of evidence A multicentre, prospective RCT showed that the incidents of surgical site infection and urinary tract infection were similar in those receiving a single dose broad spectrum antibiotic at induction of anaesthesia and those receiving antibiotics 12 hourly for 3-5 days.

Recommendation Use single-dose, rather than multi-dose, peri-operative prophylactic antibiotics in routine renal transplant recipients.

LE 1b

Strength rating Strong

3.1.4.6

Is there a role for specific fluid regimes during renal transplantation and central venous pressure measurement in kidney transplant recipients? Careful peri- and post-operative fluid balance is essential for optimal renal graft function. There is no evidence determining if crystalloids or colloids are better for intravenous fluid management during renal transplant surgery, however colloids may be immunogenic. If normal saline (0.9%) is used, monitoring for metabolic acidosis is recommended in the peri-operative period. A prospective double-blind RCT compared normal saline to lactated Ringer’s solution as intra-operative intravenous fluid therapy. Serum creatinine at day three post-surgery did not differ between the two groups. However, Ringer’s lactate caused less hyperkalaemia and metabolic acidosis than normal saline. Balanced solutions may be the optimal and safer option for intraoperative intravenous fluid therapy [96]. Central venous pressure (CVP) measurement helps anaesthetists guide fluid management. A small prospective non-blinded RCT compared two normal (0.9%) saline regimens: constant infusion (10-12 mL/kg-1/h-1 from start of surgery until reperfusion) and CVP-based infusion (target CVP appropriate to stage of operation) [97]. Central venous pressure directed infusion produced a more stable haemodynamic profile, better diuresis and early graft function. Directed hydration may decrease DGF rates and CVP measurement may help optimise early graft function.

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Summary of evidence A small (n=51) prospective RCT found that use of Ringer’s lactate solution was associated with less hyperkalaemia and acidosis compared with normal saline in patients undergoing kidney transplantation. A small (n=40) prospective RCT comparing constant infusion vs. CVP found that CVP produced a more stable haemodynamic profile, better diuresis and early graft function. Recommendations Optimise pre-, peri- and post-operative hydration to improve renal graft function. Use balanced crystalloid solutions for intra-operative intravenous fluid therapy. Use target directed intra-operative hydration to decrease delayed graft function rates and optimise early graft function.

LE 1b

1b

Strength rating Strong Weak Strong

3.1.4.7 Is there a role for dopaminergic drugs, furosemide or mannitol in renal transplantation? Low-dose dopamine (LDD) has been used in renal transplantation due to a perceived improvement in urine output and early graft function. Use of LDD in kidney donors is outside of the scope of this section. Conflicting results prevent a consensus statement on routine use of LDD in transplant recipients. A small (n=20) prospective randomised cross-over study in deceased donor renal transplantation suggested significant improvements in urine output and creatinine clearance in the first nine hours post-surgery without adverse events [98]. By contrast, a retrospective comparison of LDD in the first twelve hours post-deceased donor renal transplantation showed no difference in diuresis or kidney function, but those administered LDD (n=57) had increased heart rates, longer intensive therapy unit stay and higher six-month mortality than those not treated with LDD (n=48) [99]. Considerable variation exists in the use of diuretics during renal transplant recipient surgery and there is little evidence to suggest any benefit from their use [100]. No evidence on the use of mannitol during renal transplant recipient surgery was found during the panel’s literature search. Use of mannitol in kidney donors is outside the scope of this section. Summary of evidence A retrospective comparative study of LDD treated vs. non-treated renal transplantation patients concluded that LDD administration did not improve kidney function in the first twelve hours post renal transplantation, but did result in increased heart rates, longer intensive therapy unit stay and higher six-month mortality in those receiving LDD.

Recommendation Do not routinely use low-dose dopaminergic agents in the early post-operative period.

LE 2b

Strength rating Weak

3.1.5 Surgical approaches for first, second, third and further transplants Transplant (bench/back-table) preparation is a crucial step in the transplantation process. The kidney must be inspected whilst on a sterile ice slush, removing peri-nephric fat when possible to permit inspection of the quality of the organ and to exclude exophytic renal tumours. Biopsy of the kidney on the back-table may be performed to help in the multifactorial decision-making process regarding the quality and usage of the kidney for both single and/or dual transplantation. Suspicious parenchymal lesions also require biopsy. Techniques for intra-operative kidney biopsy are discussed in section 3.1.3. The number, quality and integrity of renal vessels and ureter(s) should be established and lymphatics at the renal hilum ligated. The quality of the intima of the donor renal artery should be evaluated. Branches of the renal artery not going to the kidney or ureter(s) should be tied. In deceased donor kidney transplantation the quality of the aortic patch should be determined. If severe atheroma of the patch, ostium or distal renal artery is seen then the aortic patch and/or distal renal artery can be removed to provide a better quality donor renal artery for implantation. Back table reconstruction of multiple donor arteries is discussed in section 3.1.5.1. The length of the renal vein should be evaluated. Renal vein branches should be secured/tied. For a deceased donor right kidney, lengthening the renal vein on the back table may be performed if needed with donor inferior vena cava (IVC) [101]. Techniques for lengthening a short living donor right renal vein from donor gonadal vein or recipient saphenous vein require pre-operative planning and specific consent (discussed in section 3.1.5.1).

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The length, quality and number of the ureter(s) should be established. The peri-pelvic and proximal peri-ureteral tissue in the ‘golden triangle’ should be preserved. Recommendation Assess the utility (including inspection) of the kidney for transplantation before commencement of immunosuppression and induction of anaesthesia for deceased donor kidney transplantation.

Strength rating Strong

3.1.5.1 Single kidney transplant - living and deceased donors The standard surgical approach for first or second single kidney transplant (SKT) operations remains open kidney transplant (OKT). Emerging surgical technologies using minimal access surgical approaches have been developed and the different surgical approaches (minimally invasive open, laparoscopic and robot-assisted) were compared in a systematic review [102]. An extra-peritoneal approach to either iliac fossa should be used as the operative approach in most first or second SKT operations. There is no evidence to prefer placement of a left or right kidney into either iliac fossa [103]. Peri-iliac vessel lymphatics should be ligated to try and prevent post-operative lymphocele. Appropriate segments of iliac artery and vein should be mobilised to facilitate appropriate tension-free vascular anastomoses and the final positioning of the transplanted kidney. There is evidence supporting the benefits of cooling the kidney surface during implantation [104]. Recommendations Choose either iliac fossa for placement of a first or second single kidney transplant. Ligate peri-iliac vessel lymphatics (lymphostasis) to reduce post-operative lymphocele.

Strength rating Weak Weak

A variety of techniques have been described to help with the anastomosis of a short renal vein. This is most commonly encountered with a right kidney, especially from a living donor. To achieve equivalent outcomes with right kidneys appropriate surgical technical manoeuvres may be needed to optimise right kidney implantation. A number of studies suggest marginally worse outcomes with use of the right compared to left kidney. two large registry studies demonstrate a slightly higher risk of early graft failure using right compared to left kidneys from living donors [105-107]. A registry study of 2,450 paired kidneys, donated after cardiac death, observed with right kidneys: more early surgical complications; an increased risk in DGF (Odds Ratio [OD] 1.46); and inferior one year graft survival (OD 1.62), but not at subsequent time points [105]. However, surgical techniques used to compensate for a right kidney, anastomosis time and surgeon experience were not recorded. A recent registry study of 87,112 deceased-donor kidney recipient pairs reported a modest increase in DGF (adjusted OD 1.15) and all-cause graft failure (adjusted hazard ratio 1.07), within the first six months, associated with use of the right kidney, but there was no association with recipient mortality [108]. Furthermore, data from cohort studies [101, 103] and one registry study [104] suggest equivalent outcomes with either left or right deceased donor kidneys. Meta-analysis of data from one RCT and fourteen cohort studies suggested equivalent graft outcomes [109]. Overall, these findings do not support declining an organ for kidney transplantation based on laterality of kidney offered. Techniques to manage a short renal vein can be addressed in the donor and/or recipient. Ligation of internal iliac vein(s) may be necessary to elevate the iliac vein and avoid tension on the renal vein anastomosis [103]. Transposition of the iliac artery and vein may enhance the position for the venous anastomosis [110]. The right renal vein may be lengthened. With deceased donor kidneys this is usually done with donor IVC [111]. In living donors, lengthening of the renal vein may be achieved with donor gonadal vein retrieved at donor nephrectomy [112] or with recipient saphenous vein [113], although both require specific consent and in general the other aforementioned techniques are preferred. Summary of evidence Prospective cohort studies demonstrated that: • transposition of the recipient iliac vein is an appropriate technical solution to compensate for the short length of the renal vein in right kidney LDN (n=43); • the living donor right kidney renal vein can be successfully lengthened using donor gonadal vein (n=17) or recipient saphenous vein (n=19).

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Recommendation Assess the length of the donor renal vein and if it is short consider one of a variety of surgical techniques to optimise the venous anastomosis.

Strength rating Weak

A history suggesting previous iliac or femoral vein thrombosis should initiate pre-operative imaging to establish patency of one iliac vein and the IVC. An intra-operative finding of an unexpected iliac vein and/or vena cava thrombosis may lead to abandonment of implantation. With pre-operative planning, native renal (orthotopic) or superior mesenteric vein or gonadal vein collaterals can be used. The external or common iliac arteries are equally good for arterial anastomosis. The internal iliac artery is more frequently affected by atherosclerosis than the external or common iliac arteries. End-to-side anastomosis of donor renal artery to recipient external and/or common iliac artery is recommended in general over an end-toend anastomosis to the internal iliac artery. The only RCT comparing these techniques suggests no difference [114]; however, the study was limited by small numbers and a high (8%) overall renal artery thrombosis rate. The sites of the vascular anastomosis should be chosen carefully according to the length of the renal artery and vein to avoid kinking of the vessels when the kidney is placed into its final location, usually in the iliac fossa. The site of the arterial anastomosis should avoid atheromatous plaques in the iliac artery to decrease the risk of iliac artery dissection. The intima of the donor and recipient arteries should be checked prior to commencing the arterial anastomosis to ensure that there is no intimal rupture/flap. If this is found it must be repaired prior to, or as part of, the arterial anastomosis. A Carrel patch is usually maintained on a deceased donor renal artery although it can be removed if there is either severe ostial atheroma/stenosis (with good quality proximal renal artery) or if the length of the renal artery is too long for the appropriate implantation site on the iliac artery (which is more common with the right renal artery). Multiple renal arteries supplying a deceased donor kidney can be maintained on a Carrel patch (of appropriate length) and implanted as a single anastomosis. In living donor transplantation, multiple renal arteries require a variety of strategies to achieve optimum re-perfusion [100]. Two arteries can be implanted separately or to achieve a single anastomosis: a very small second artery (especially if supplying the upper pole) may be sacrificed; the two arteries may be joined together (as a trouser graft); or the smaller artery can be anastomosed onto the side of the main artery (end-to-side anastomoses). A lower polar artery may be re-vascularised via anastomosis to the inferior epigastric artery [115]. In living donor transplantation where three or more donor arteries exist, consideration should be given to alternate kidney donors. In circumstances using a living donor kidney with three or more donor arteries, strategies include a combination of the above techniques or, after appropriate consent, use an explanted (recipient’s own) internal iliac artery graft [116] or saphenous vein graft [117]. In cases where an iliac artery prosthetic replacement has previously been carried out because of severe symptomatic iliac atheroma, the renal artery should be implanted into the prosthesis. Administration of systemic heparin should be considered prior to clamping of a vascular prosthesis [118]. A variety of sutures and suturing techniques for the vascular anastomosis are described, but in general practice, a 5/0 and 6/0 non-absorbable mono-filament polypropylene suture(s) are used for the renal vein and renal artery anastomosis. Despite this, there is no evidence to recommend one suturing technique over another to prevent, for example, transplant artery stenosis. Use of an expanded polytetrafluroethylene suture compared to standard polypropylene suture may reduce blood loss due to a better needle/thread ratio [119]. In third or further transplants the surgical approach must be planned pre-operatively so that appropriate arterial inflow and venous outflow exists with adequate space to implant the new kidney [120, 121]. Nephrectomy of an old transplant kidney may be required prior to transplantation or at the time of transplantation [120]. Mobilisation of the common or internal iliac artery, internal iliac vein or IVC may be required. An intra-peritoneal approach (via the iliac fossa or midline) may be required [122]. Rarely orthotopic transplantation is needed [120, 123]. Evidence suggests that minimising the anastomosis time and/or rewarming time results in reduced DGF [124]. The effect on long term graft function is uncertain, but may also be impacted by short anastomosis time [125].

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Summary of evidence A small RCT (n=38) comparing end-to-end anastomosis to the internal iliac artery vs. end-to-side anastomosis to the external iliac artery found that both techniques showed similar results in the postoperative period and at three-years follow-up. Cohort studies have demonstrated third or further transplants are a valid therapeutic option with reasonable short- and long-term patient and graft survival. Recommendations Use the external or common iliac arteries for an end-to-side arterial anastomosis to donor renal artery. Use an end-to-end anastomosis to the internal iliac artery as an alternative to external or common iliac arteries. Check the intima of the donor and recipient arteries prior to commencing the arterial anastomosis to ensure that there is no intimal rupture/flap. If this is found it must be repaired prior to/as part of the arterial anastomosis. Pre-operatively plan the surgical approach in third or further transplants, to ensure that appropriate arterial inflow and venous outflow exists with adequate space to implant the new kidney.

LE 1b

3

Strength rating Weak Weak Strong

Strong

3.1.5.2 Robot-assisted kidney transplant surgery Robot-assisted kidney transplant (RAKT) surgery using living donor kidneys has been evaluated in multi-centre prospective non-randomised studies (using IDEAL consortium principles) [126]. Single-centre prospective nonrandomised studies are on-going addressing RAKT with use of deceased donor kidneys. Both trans- and extra-peritoneal approaches for RAKT are described. Potential advantages of RAKT may exist (decreased postoperative pain, incision length and lymphocele rate). Potential issues with RAKT are the exclusion of recipients with severe atherosclerosis or third (or further) kidney transplants, a higher than expected rate of DGF and a small number of reported early arterial thromboses despite carefully selected cases [127]. The learning curve for RAKT has been reported to be 35 cases for experienced surgeons in a retrospective multicentre series of 187 patients undergoing RAKT [128]. Complication and DGF rates decreased significantly and plateaued after the first 20 cases. The rate of Clavien-Dindo grade III/IV complications was 14% during the first ten RAKTs, but only 3% after this [128]. The rate of arterial graft thrombosis (1.6%) was comparable with that for open kidney transplant (0.5 - 3.5%) [128]. A ten year single-centre retrospective analysis of 239 obese RAKT patients concluded that RAKT can be safely performed in obese patients with minimal risk of developing a surgical site infection [129]. A graft failure rate of 7.1% was reported during follow-up mostly due to acute rejection. Patient and graft survival was 95% and 93% at three years, respectively [129]. Evidence is too premature to recommend RAKT outside of appropriately mentored prospective studies. 3.1.5.3 Dual kidney transplants Dual kidney transplant (DKT) is performed when the quality of a single deceased donor kidney is thought to be insufficient for appropriate long-term graft function and that the outcome with both kidneys would be better. A variety of surgical techniques have been described to implant the pair of donor kidneys [130]. These include unilateral extra-peritoneal (UEP) or intra-peritoneal (UIP) and bilateral extra-peritoneal (BEP) or intra-peritoneal (BIP) that can be via a midline [131] or two lateral incisions. The aim of a unilateral approach is to leave the contralateral iliac fossa intact for future transplantation in the event of graft loss and to reduce CIT for the second kidney transplant [132]. The unilateral approach may require mobilisation and division of the internal iliac vein to facilitate the two renal veins to iliac vein anastomoses. Modifications of the unilateral technique include single renal artery and vein anastomoses (with bench reconstruction) to further reduce CIT for the second kidney [133-135]. Dual kidney transplant takes longer and has higher blood loss than SKT regardless of the technique used. Data suggest shorter operative time and hospital stay with UEP compared to BEP [136], but other data suggest similar outcomes from all DKT techniques. No RCT exists to recommend one technique for all patients or situations. En-bloc retrieval is performed when kidneys are retrieved from children weighing < 15 kg. Depending on the size of the donor kidney and size and weight of the adult recipient(s), en-bloc transplantation of the two kidneys may be performed or, if appropriate, the aorta and IVC patch may be divided for SKT [137]. 3.1.5.4 Ureteric implantation in normal urinary tract Ureteric anastomotic techniques described for renal transplant recipients with no underlying urological abnormality include: extra (Lich-Gregoir) or intra (Leadbetter-Politano) vesical uretero-neo-cystotomy and uretero-ureterostomy using native ureter. A meta-analysis [138] of two RCTs and 24 observational studies

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favoured the extra-vesical Lich-Gregoir technique to an intravesical approach leading to reduced overall complications (specifically urine leak, stricture and post-operative haematuria). Fewer urinary tract infections (UTIs) were observed with the extravesical approach when compared with the intra-vesical technique in one RCT [139]. Pyelo- or uretero-ureterostomy to the ipsilateral native ureter has been described as a primary technique in recipients with non-refluxing native ureters [140]. A meta-analysis suggested ureteric stricture, obstruction, and stone formation were more common after uretero-ureterostomy whereas vesicoureteral reflux and UTIs were more common after uretero-neo-cystostomy [141]. The donor ureter should be kept as short as possible with peri-ureteric fat preserved to ensure adequate ureteric blood supply. The location on the bladder to position an extra-vesical anastomosis was shown in one small RCT to be advantageous at the posterior bladder rather than anterior position to facilitate future endoscopic manipulation if needed, and reported less hydronephrosis post stent removal [142]. In cases where donor ureter has been damaged at retrieval then pyelo-native-ureterostomy or pyelo-neo-cystotomy can be performed. Mono-filament absorbable sutures should be used for the urinary anastomosis to prevent stone formation around the suture material [143]. Summary of evidence A meta-analysis of two RCTs and 24 observational studies favoured the extra-vesical Lich-Gregoir technique for reduced overall complications. A multi-centre prospective comparison study found the incidence of overall complications was similar for pyelo- and uretero-ureteral anastomosis and that for both procedures no graft was lost due to urological complications.

Recommendations Perform Lich-Gregoir-like extra-vesical ureteric anastomosis technique to minimise urinary tract complications in renal transplant recipients with normal urological anatomy. Pyelo/uretero-ureteral anastomosis is an alternative especially for a very short or poorly vascularised transplant ureter.

LE 1a 2b

Strength rating Strong Strong

Transplant ureteric anastomosis can be performed with or without a ureteric stent. If a stent is placed a second procedure is generally required for removal. A Cochrane review [144] concluded that stents are recommended to reduce major urological complications, especially urinary leak. The optimal timing for stent removal has yet to be defined [145]. A meta-analysis of five RCTS including 568 kidney transplantation patients showed a significant reduction in UTIs for early (≤ 7 days) vs. late removal (≥ 14 days) [146]. No significant differences where observed between the two groups in relation to post-operative complications such as ureteral stricture, ureteral obstruction, and ureteral leakage [146]. A second meta-analysis including 3,612 patients also reported a significant reduction in UTIs with early stent removal (< 3 weeks) vs. late removal (> 3 weeks) [147]. No significant differences where observed between the two groups regarding the incidents of ureteral stenosis and ureteral leakage [147]. Most commonly, stents are removed with local anaesthetic flexible cystoscopy unless there is a need to combine with another procedure warranting general anaesthetic. Various techniques to reduce the morbidity of a second procedure involve tying the stent to the catheter or use of percutaneous stents [148]. Recommendation Use transplant ureteric stents prophylactically to prevent major urinary complications.

Strength rating Strong

Duplex ureters are not infrequently identified at organ retrieval/kidney benching or during work-up for LDN [149, 150]. Duplex ureters can be anastomosed together and then joined to the bladder as one unit (double pant) or kept as two separate anastomoses. This also applies to the two single ureters in DKT in adults or with en-bloc transplantation from paediatric donors. The arguments for two separate ureteric anastomoses to the bladder are that an already tenuous blood supply may be further compromised with added suturing and handling, and if there is an issue with one ureter the other should remain unaffected. The advantages to forming one single (two ureter) anastomosis to the bladder are that only one cystotomy is needed; it may be faster and complications may be reduced. There is a lack of high-quality evidence relating to duplex ureters. Recommendation Use the same surgical principals for single ureters to manage duplex ureters and anastomose them either separately or combined.

RENAL TRANSPLANTATION - TEXT UPDATE 2021

Strength rating Strong

17

3.1.5.5 Transplantation/ureteric implantation in abnormal urogenital tract The following points should be considered when performing kidney transplantation in the abnormal urogenital tract: • In patients with an ileal conduit, a kidney transplant may be placed upside down to align the ureter to the conduit and avoid a redundant ureter [151]. • The technique used to implant transplant ureter(s) into an ileal conduit is the same as the method used with native ureter(s) (Bricker; Wallace). • In bladder augmentation or continent pouches, ureters should be implanted with a tunnel technique or extra-vesically (Lich-Gregoir). The latter is favoured in most patients. • In patients with a Mitrofanoff catheterisable stoma or continent ileo-caecal pouch with catheterisable stoma, consideration should be given to the positioning of the catheterisable stoma (umbilical or iliac fossa - usually right-side) with clear communication with the transplant surgeons so that the position of any future transplant kidney is not compromised. If an intra-peritoneal placement of a future kidney transplant is likely, then placement of a Mitrofanoff exiting in the iliac fossa is preferable at the umbilicus. If a future kidney transplant is likely in the right iliac fossa then placement of a Mitrofanoff exiting at the umbilicus or left iliac fossa may be preferable. 3.1.6 Donor complications Living-donor nephrectomy, like any other intervention, is potentially associated with complications and mortality. However, the fact that the operation is performed on a healthy individual amplifies the relevance of any complications. Potential complications should be included in the process of informed consent. Reported surgical mortality is 0.01% to 0.03% with no apparent alteration due to changes in surgical techniques or donor selection in recent years [152, 153]. According to a recent systematic review (190 studies) and meta-analysis (41 studies) on complications in minimally invasive LDN, reporting on a total of 32,308 LDNs, intra-operative complications occur in 2.2% (the most common being bleeding in 1.5% and injury to other organs in 0.8%) and post-operative complications occur in 7% (infectious complications in 2.6% and bleeding in 1%) [152]. Conversion to open surgery was reported in 1.1%, half due to bleeding and half due to injury to other organs. Surgical re-interventions occurred in 0.6%; the majority due to bleeding or to evacuate a haematoma [152]. A low trigger for conversion or re-operation should be observed in order to minimise the risk of serious complications. A recent review looked for complications in 14,964 LDNs performed in the U.S. from 2008-2012 and found an overall peri-operative complication rate of 16.8%, gastrointestinal (4.4%), bleeding (3.0%), respiratory (2.5%), surgical/anaesthesia-related injuries (2.4%), and “other” complications (6.6%). Among the sample, 2.4% required intensive care and in-hospital mortality was 0.007% [16]. Major Clavien Classification of Surgical Complications grade IV or higher affected 2.5% of donors. Risk factors for Clavien grade IV or higher events included obesity (adjusted odds ratio [aOR] 1.55, p = 0.0005), pre-donation haematologic (aOR 2.78, p = 0.0002), psychiatric conditions (aOR 1.45, p = 0.04) and robotic nephrectomy (aOR 2.07, p = 0.002). An annual centre volume > 50 (aOR 0.55, p < 0.0001) was associated with lower risk [16]. 3.1.6.1 Long-term complications Long-term complications are mostly related to the single-kidney condition. Renal function in living donors decreases after donation before improving for many years; however, in the long run it shows signs of slight deterioration [154-156]. There is a steady increase in the incidence of proteinuria; hypertension post-transplant having been shown as the main cause of increased albumin excretion [157]. The overall incidence of end-stage renal disease (ESRD) (0.4-1.1%) does not differ from the general population [154, 155, 158, 159]. According to a recent large retrospective study, the majority of ESRD developing after living kidney donation is due to new-onset disease that would have affected both kidneys [160]. However, there are some identified risk factors for deterioration of renal function after donation. According to a recent study that evaluated 119,769 live kidney donors in the United States, obese (BMI > 30) living kidney donors have a 1.9-fold higher risk for ESRD compared to their non-obese counterparts [161]. Long-term risk of death is no higher than for an age- and co-morbidity-matched population [153, 158]. Health related quality of life (HRQoL), including mental condition, remains on average better than the general population after donation [158, 159, 162]. However, some donors experience significant deterioration in their perceived QoL [162]. While global HRQoL is comparable or superior to population normative data, some factors identifiable around time of donation including longer recovery, financial stressors, younger age, higher BMI, lower education, smoking and higher expectations prior to donation, may identify donors more likely to develop poor HRQoL, providing an opportunity for intervention [158, 159, 162]. It is paramount that a careful

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risk–benefit assessment is done and that proper information is given to the prospective donor, this should also include recommendations on health-promoting behaviour post-donation [163]. Summary of evidence LE A systematic review and meta-analysis on complications in minimally invasive LDN concluded that the 1a techniques used for minimally invasive LDN are safe and associated with low complication rates. Survival rates and risk of end-stage renal disease are similar to those in the general population whilst 2b donors HRQoL remains on average better than the general population.

Recommendations Restrict living donor nephrectomy to specialised centres. Offer long-term follow-up to all living kidney donors.

Strength rating Strong Strong

3.1.7 Recipient complications 3.1.7.1 General complications Surgical complications during and after kidney transplantation may expose the recipient to an increased risk of morbidity and mortality. The incidence and management of such complications is therefore of primary importance [138, 145, 164-176]. We herein describe in detail the most common surgical complications in renal transplantation. 3.1.7.2 Haemorrhage Haematomas are usually a minor complication in renal transplantation. Their incidence is reported to be between 0.2-25% [177, 178]. Small and asymptomatic haematomas do not usually require any intervention. In case of larger haematomas, clinical signs and symptoms due to external pressure with graft dysfunction and/or thrombotic graft vessel complications can be present. These cases may be treated by percutaneous drainage under computed tomography (CT) or ultrasound (US) guidance or may require surgical treatment [177]. 3.1.7.3 Arterial thrombosis Transplant renal artery thrombosis is a rare complication with a prevalence ranging from 0.5-3.5% [179]. Usually, it is a consequence of a technical error during the anastomosis although other causes may be related to both the donor and recipient’s artery condition (i.e. atherosclerosis), intimal rupture during kidney harvesting, acute rejection episodes, external compression by haematoma or lymphocele, hypercoagulative state, severe hypotension, and toxicity of immunosuppressive agents (cyclosporine or sirolimus) [180]. The clinical manifestations are acute reduction of urine output and the elevation of renal function tests, often resulting in graft loss [177]. The diagnosis is obtained with eco-colour-Doppler [177]. Surgical exploration is usually recommended to evaluate the status of the graft. In the rare event the graft appears salvageable, a thrombectomy must be performed. In this situation, the iliac artery is clamped and an arteriotomy vs. a dissection of the vascular anastomosis must be performed in order to remove the clot. The graft can be flushed in-situ and re-vascularised [177]. Unfortunately, in the majority of the situations, the graft is not perfused and therefore an allograft nephrectomy must be performed [177, 181]. Alternatively, thrombolytic agent administration through a catheter directly into the transplant renal artery can be an efficient treatment, after the first ten to fourteen post-transplantation days [177]. Summary of evidence The diagnosis of renal artery thrombosis depends on eco-colour-Doppler followed by surgical exploration to assess the status of the graft. Thrombectomy in the case of a viable graft and allograft nephrectomy in the case a non-viable graft are the treatment options for renal artery thrombosis.

Recommendations Perform ultrasound-colour-Doppler in case of suspected graft thrombosis. Perform surgical exploration in case of ultrasound finding of poor graft perfusion. Perform a surgical thrombectomy in case of a salvageable graft if arterial thrombosis is confirmed intra-operatively. Perform an allograft nephrectomy in case of a non-viable graft.

RENAL TRANSPLANTATION - TEXT UPDATE 2021

LE 2b 2b

Strength rating Strong Strong Weak Strong

19

3.1.7.4 Venous thrombosis Transplant renal vein thrombosis is an early complication (prevalence 0.5-4%) and one of the most important causes of graft loss during the first post-operative month [182]. The aetiology includes technical errors and/or difficulties during surgery [177] and the hypercoagulative state of the recipient [183, 184]. Colour-Doppler-flowultrasonography shows absence of venous flow with an abnormal arterial signal (usually a plateau-like reversed diastolic flow). Furthermore, it is common to see an enlargement of the graft due to venous congestion [185]. Surgical exploration is usually recommended despite the fact that the majority of the cases will result in graft loss. In those cases where the venous thrombosis has not resulted in kidney loss at surgical exploration, a venotomy with surgical thrombectomy after clamping the iliac vein can be performed. Alternatively, an explantation and subsequent re-implantation can be considered [177]. Thrombolytic agents can also be used; however, their results have not been satisfactory [177, 186, 187]. Summary of evidence The diagnosis of renal vein thrombosis depends on colour-Doppler-flow-ultrasonography followed by surgical exploration to assess the status of the graft. Thrombectomy in the case of a viable graft and allograft nephrectomy in the case a non-viable graft are the treatment options for renal vein thrombosis.

Recommendations Perform ultrasound-colour-Doppler in case of suspected graft thrombosis. Perform surgical exploration in case of ultrasound finding of poor graft perfusion. If venous thrombosis is confirmed intra-operatively, perform a surgical thrombectomy in case of a salvageable graft or an allograft nephrectomy in case of a non-viable graft. Do not routinely use pharmacologic prophylaxis to prevent transplant renal vein thrombosis.

LE 2b 2b

Strength rating Strong Weak Weak Strong

3.1.7.5 Transplant renal artery stenosis. The incidence of transplant renal artery stenosis is 1-25% [188, 189]. Risk factors include small calibre and atherosclerosis of the donor artery, trauma to donor artery at procurement, absence of arterial patch, suturing technique (interrupted vs. continuous), and damage to the iliac artery during transplantation [190, 191]. It is more common at the site of the anastomosis [190, 191]. It can be suspected in case of arterial hypertension refractory to medical treatment and/or an increase in serum creatinine without hydronephrosis or urinary infection. The diagnosis is performed by US-colour-Doppler, showing a peak systolic velocity (PSV) of > 200 cm/s in the graft renal artery [190]. In cases of doubt a magnetic resonance angiogram or a CT angiogram can be performed [192]. It is important to determine whether the stenosis is haemodynamically significant or not. Usually, a stenosis of over 50% is considered a risk for kidney impairment [193]. In case of mild stenosis (< 50%) and absence of symptoms with no deterioration of the allograft, management is normally conservative; although, a strict follow-up with US-colour-Doppler and clinical parameters has to be adopted due to the possible risk of graft failure [190]. In cases of clinically significant stenosis and/or > 50% on US-colour-Doppler, a confirmatory angiogram should be performed. If confirmed and a decision to treat is taken, treatments include percutaneous transluminal angioplasty/stent or surgical intervention. Interventional radiology is typically the first choice although patients considered unsuitable for radiological angioplasty due to recent transplant, multiple, long and narrow stenosis, or after failure of angioplasty may benefit from surgical treatment [190, 191]. Summary of evidence Suspect transplant renal artery stenosis in case of refractory arterial hypertension and/or increasing serum creatinine without hydronephrosis/infection. The diagnosis for transplant renal artery stenosis is by US-colour-Doppler, showing a peak systolic velocity of > 200 cm/s in the graft renal artery. Interventional radiology is the first-line treatment option for transplant renal artery stenosis; however, in patients considered unsuitable for radiological angioplasty surgical treatment may be considered.

Recommendations Perform ultrasound-colour-Doppler to diagnose an arterial stenosis, in case of undetermined results on ultrasound consider a magnetic resonance or computed tomography angiogram.

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LE 3 2a 3

Strength rating Strong

RENAL TRANSPLANTATION - TEXT UPDATE 2021

Perform percutaneous transluminal angioplasty/stent, if feasible, as first-line treatment for an arterial stenosis. Offer surgical treatment in case of recent transplant, multiple, long and narrow stenosis, or after failure of angioplasty.

Strong Strong

3.1.7.6 Arteriovenous fistulae and pseudo-aneurysms after renal biopsy Percutaneous biopsy may result in arteriovenous (AV) fistulae and/or intra-renal pseudo-aneurysms in 1-18% of cases [194]. The aetiology of the AV fistula is related to the simultaneous injury of adjacent arterial and venous branches. A pseudo-aneurysm occurs when only the arterial branch is damaged. Both conditions are diagnosed with US-colour-Doppler [177]. The majority of AV fistulae are asymptomatic, resolving in one to two years spontaneously, whilst approximately 30% of them persist and become symptomatic. Typically, the symptoms are hypertension, haematuria, and graft dysfunction due to shunting between arterial and venous vessels. There is an increased risk of spontaneous rupture in case of enlarging pseudo-aneurysms. For both AV fistulae and pseudo-aneurysm, angiographic selective or super selective embolisation represents the treatment of choice [195]. Partial or radical allograft nephrectomy is currently considered the last option [177]. Recommendations Perform a ultrasound-colour-Doppler if a arteriovenous fistulae or pseudo-aneurysm is suspected. Perform angiographic embolisation as first-line treatment in symptomatic cases of arteriovenous fistulae or pseudo-aneurysm.

Strength rating Strong Strong

3.1.7.7 Lymphocele Lymphocele is a relatively common (1-26%) complication [196]. There is a significant aetiological association with diabetes, mammalian target of rapamycin (mTOR) inhibitors (i.e. sirolimus) therapy, and acute rejection [197]. For large and symptomatic lymphocele, laparoscopic fenestration is associated with the lowest overall recurrence (8%) and complication (14%) rate compared to open surgery and aspiration therapy [198]. Placement of a percutaneous drain (i.e. Pig-Tail) is an option with a success rate as high as 50% [163]. Percutaneous aspiration can be performed although the recurrence rate can be as high as 95% [198], with an increased risk of local infection (6-17%) [198]. Furthermore, sclerosant agents such as ethanol, fibrin sealant, gentamicin, or octreotide reduce the recurrence rate compared to simple aspiration [198, 199]. Recommendations Strength rating Perform percutaneous drainage placement as first-line treatment for large and symptomatic Strong lymphocele. Perform fenestration when percutaneous treatments fail. Strong 3.1.7.8 Urinary leak Urinary leakage occurs in 0-9.3% of cases [200]. Anastomotic urine leaks can be ureteral or vesical [201]. Ureteral necrosis and/or suture failure are the most important causes [202, 203]. Non-technical risk factors include recipient age, number of renal arteries, site of arterial anastomosis, occurrence of acute rejection episodes, bladder problems, and immunosuppressive regimen [204]. Urinary leak can be suspected by the urine output and the creatinine level in the drain fluid [202]. In order to decrease the risk of ureteral necrosis, it is important to preserve vascularisation of the distal ureter [202]. Furthermore, the routine use of a JJ-stent is recommended [203, 205]. The management of urinary leak depends on the location (renal pelvis, proximal or distal ureter, and bladder), the time of appearance and the volume of the leak. For early and low volume urine leaks the treatment may be conservative (i.e. urethral catheter, percutaneous nephrostomy and JJ-stent) [206]. In case of failure of the conservative management, or massive leak, surgical repair must be undertaken. Ureteral re-implantation directly to the bladder or to the native ureter provide similar results [141, 206]. Summary of evidence Suspect urinary leakage based on the urine output and the creatinine level in the drain fluid. For early and low volume urine leaks conservative management may be considered. Surgical repair should be undertaken when conservative management fails or massive urine leak occurs.

RENAL TRANSPLANTATION - TEXT UPDATE 2021

LE 3 3 2b

21

Recommendations Manage urine leak by JJ-stent and bladder catheter and/or percutaneous nephrostomy tube. Perform surgical repair in cases of failure of conservative management.

Strength rating Strong Strong

3.1.7.9 Ureteral stenosis Ureteral stenosis is a common complication in recipients, with an incidence of 0.6-10.5% [207]. Early stenosis (within three months of surgery) is usually caused by surgical technique or compromised ureteral blood supply during surgery. Late stenosis (after > six months) is provoked by infection, fibrosis, progressive vascular disease and/or rejection [202, 208]. Clinically significant ureteral stricture should be considered when persistent hydronephrosis on US occurs in association with impaired renal function. The first approach in the management of stricture is the placement of a percutaneous nephrostomy tube with an antegrade pyelogram [207]. The following treatment options depend mainly on the timing, recoverable kidney function, anatomy of the stricture, patient body habitus/comorbidities, and surgeon preference. Strictures < 3 cm in length may be treated endoscopically either with percutaneous balloon dilation or antegrade flexible ureteroscopy and holmium laser incision. In this scenario the success rate approaches 50%; although, maximum success is obtained for strictures < 1 cm [209-211]. In case of a recurrence after a primary endourological approach and/or stricture > 3 cm in length, surgical reconstruction should be performed [208] including direct ureteral re-implantation, pyelo-vesical re-implantation (with or without psoas hitch and/or Boari Flap) or in cases with a normal native ureter, uretero-ureterostomy [212, 213]. Long-term graft and patient survival are not significantly affected [214]. Summary of evidence Clinically significant ureteral stricture should be considered when persistent hydronephrosis on US occurs in association with impaired renal function. The first approach in the management of a stricture is the placement of a percutaneous nephrostomy tube with an antegrade pyelogram. Strictures < 3 cm in length may be treated endoscopically. For strictures > 3 cm in length or those which have reoccurred following a primary endourological approach surgical reconstruction should be performed. Recommendations In case of ureteral stricture, place a nephrostomy tube for both kidney decompression and stricture diagnosis via an antegrade pyelogram. Manage strictures < 3 cm in length either with surgical reconstruction or endoscopically (percutaneous balloon dilation or antegrade flexible ureteroscopy and holmium laser incision). Treat late stricture recurrence and/or stricture > 3 cm in length with surgical reconstruction in appropriate recipients.

LE 3 2b 3 2b

Strength rating Strong Strong

Strong

3.1.7.10 Haematuria The incidence of haematuria ranges from 1-34% [200]. According to the literature, the Lich-Gregoire technique provides the lowest incidence of haematuria. Furthermore, meticulous haemostasis during re-implantation results in minimal bleeding [138, 200, 201]. Bladder irrigation is the first-line treatment. Some cases require cystoscopy with evacuation of clots and/or fulguration of bleeding sites [200]. 3.1.7.11 Reflux and acute pyelonephritis The frequency of vesicoureteral reflux is between 1-86% [200, 215]. Acute graft pyelonephritis occurs in 13% of graft recipients. Patients with lower tract urinary infections and cytomegalovirus (CMV) infection present a higher risk of acute graft pyelonephritis [216]. Endoscopic injection of dextranomer/hyaluronic acid copolymer may be the first approach for treatment of vesicoureteral reflux associated with acute pyelonephritis, with a success rate ranging from 57.9% after the first injection to 78.9% after the second injection [217]. Ureteral re-implantation or pyelo-ureterostomy with the native ureter is a viable second treatment option [212]. Recommendation Use an endoscopic approach as first-line treatment for symptomatic reflux.

22

Strength rating Weak

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3.1.7.12 Kidney stones Urolithiasis occurs in 0.2-1.7% of recipients [218, 219]. The most frequent causes are hyper filtration, renal tubular acidosis, recurrent UTIs, hypocitraturia, hyperuricaemia, hyperuricemia, excessive alkaline urine, persistent tertiary hyperparathyroidism and ureteral strictures [220, 221]. Another risk factor can be urinary anastomosis, with the lowest stone rate using Lich-Gregoir technique [219]. The most frequent clinical signs are fever, increased serum creatinine level, decreased urine output, and haematuria. Pain is usually not referred to due to impaired innervation. A US examination usually provides the diagnosis although a CT of the kidneys, ureters and bladder may be needed to confirm the location and size of the stone [220]. The management depends on the location and size of the stone, and the presence of obstruction. In case of obstructive stones first-line treatment includes placement of a nephrostomy tube, or in some occasions a JJ-stent [222]. Extracorporeal shock wave lithotripsy (ESWL) is usually considered the first approach for stones < 15 mm with stone-free rates varying between 40 and 80% depending on the location of the stone [222]. Ureteroscopy, including antegrade and retrograde approaches, can be considered for stones < 20 mm, with a success rate of up to 67% [140, 219, 223]. For larger stones (> 20 mm), percutaneous nephrolithotomy (PNL) can be offered with high overall effective stone-free rates. In cases of large impacted stones, uretero-ureteral anastomosis, pyelo-ureteral anastomosis, or uretero-vesical re-implantation may provide excellent results for both stone and ureteral obstruction [219]. Summary of evidence Extracorporeal shockwave lithotripsy should be considered as the first-line treatment option for stones < 15 mm. Antegrade/retrograde ureteroscopy and PNL may be considered as treatment options as they provide high stone-free rates. For larger stones (> 20 mm), PNL can be offered with a high overall effective stone-free rate.

Recommendations Evaluate the causes of urolithiasis in the recipient. Treat ureteral obstruction due to a stone with a percutaneous nephrostomy tube or JJ-stent placement. Perform shockwave lithotripsy or antegrade/retrograde ureteroscopy for stones < 15 mm. Perform percutaneous nephrolithotomy for stones > 20 mm.

LE 2b 2b 2b

Strength rating Strong Strong Strong Weak

3.1.7.13 Wound infection Wound infections occur in about 4% of cases. Risk factors include recipients > 60 years, high BMI, anaemia, hypo-albuminemia, long surgical times (> 200 min) [224]. Bacteria commonly involved are Enterobacteriaceae, Staphylococcus aureus and Pseudomonas [212]. Subcutaneous sutures, pre-dialysis transplantation, sealing or ligation of lymphatic trunks, prophylactic fenestration, reducing corticosteroid load, and avoiding sirolimus/ everolimus therapy can decrease wound complication rates [224]. 3.1.7.14 Incisional hernia Incisional hernia occurs in approximately 4% of open kidney transplantations. Risk factors include age, obesity, diabetes, haematoma, rejection, re-operation through the same transplant incision and use of m-TOR inhibitors. Mesh infection is a risk factor for incisional hernia recurrence [225]. Open and laparoscopic repair approaches are safe and effective [225]. 3.1.8 Urological malignancy and renal transplantation The following section is limited to a synopsis of three systematic reviews conducted by the EAU Renal Transplantation Panel. 3.1.8.1 Malignancy prior to renal transplantation 3.1.8.1.1 In the recipient Standard procedure for transplant candidates includes systematic screening for the presence of any active/ latent cancer or a past history of cancer. In candidates with a previous history of urological cancer, it can be challenging to decide if patients are suitable for transplantation and, if so, how long the waiting period prior to transplantation should be. To date, the waiting period has been primarily based on the Cincinnati Registry, which takes into account the type of tumour and the time between its treatment and kidney transplantation. However, the Cincinnati Registry has potential drawbacks as it does not consider the epidemiology of tumours

RENAL TRANSPLANTATION - TEXT UPDATE 2021

23

or that diagnostic and therapeutic procedures/tests have changed over time and that prognostic tools have improved. Additionally, treatment and the staging of the disease are not defined. According to a recent systematic review the risk of tumour recurrence was similar between transplantation (n=786) and dialysis (n=1,733) populations for renal cell carcinoma (RCC) and prostate cancer (PCa). This was especially true for low grade/stage PCa, for which the risk of recurrence was low and consistent with nomograms [226]. For low stage/grade RCC the recurrence rate was significant for both dialysis and renal transplantation; however, recurrences were actually contralateral RCC with no impact on patient or graft survival [226]. Testicular cancer had a low risk of recurrence but case reports highlighted the possibility of late recurrence even for stage I tumours [226]. For urothelial carcinoma, studies were mainly related to upper urinary tract carcinomas in the context of aristolochic acid nephropathy for which the rate of synchronous bilateral tumour was 10-16% and the rate of contralateral recurrence was 31-39% [226]. These findings imply that a kidney transplant candidate with a history of appropriately treated low stage/grade PCa (PSA ≤ 10, Gleason score ≤ 6 and T1/T2a) or low grade T1 RCC could be listed for renal transplantation without any additional delay compared to a cancer-free patient. However, as the level of evidence was low, more studies are needed to standardise waiting periods before renal transplantation. Summary of evidence Renal Cell Carcinoma The recurrence rates for transplanted vs. dialysed patients at 5 years were 0–8% vs. 0%, 0–27% vs. 0–9% and 0–41% vs. 0–48%, respectively. Overall five year survival rates for transplantation vs. dialysed patients were 80–100% vs. 76–100%, respectively. Prostate Cancer The recurrence rates for transplantation patients at 5 years were 0–9% and 4–20%, respectively. Overall, 1–5 year survival rates for transplantation patients ranged from 62% to 100%.

LE 2b

2b

Recommendation Strength rating List for renal transplantation patients with a history of appropriately treated low stage/grade Weak renal cell carcinoma or prostate cancer without additional delay.

3.1.8.1.2 In the potential donor kidney In the general population, RCC constitutes 3% of all malignancies, with the incidence being highest in patients aged > 60 years. The current increasing age of donors may lead to a higher number of incidental RCCs found in donor kidneys and could theoretically decrease the number of kidneys suitable for transplantation. The main surgical approach to these kidneys is ex vivo tumour excision on the back-table with an oncological margin, frozen section biopsy, bench surgery renorraphy, and finally transplantation in the conventional fashion [227]. A recent systematic review assessed the effectiveness and harms of using kidneys with small renal tumours, from deceased or living donors, as a source for renal transplantation and it reported that five year overall and graft survival rates were 92% and 95.6%, respectively [227]. Tumour excision was performed ex vivo in all cases except for two (107/109 patients), and the vast majority of excised tumours were RCCs (88/109 patients), with clear-cell subtype the most common [227]. This systematic review, although with low-level evidence, suggested that kidneys with small renal masses are an acceptable source for renal transplantation and do not compromise oncological outcomes with similar functional outcomes to other donor kidneys. Summary of evidence Tumour excision was performed ex-vivo in all cases except for two (107/109 patients). Overall survival rates at one, three and five years were 97.7%, 95.4%, and 92%, respectively. Mean graft survival rates at one, three and five years were 99.2%, 95%, and 95.6%, respectively.

Recommendation Do not discard a kidney for potential transplantation on the basis of a small renal mass alone.

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3.1.8.2 Malignancy after renal transplantation Cancer development after kidney transplant has become a major problem as it is one of the main causes of death in this population. Urological cancers, have an increased incidence after kidney transplantation partly due to the increasing age of recipients and their prolonged survival after transplantation. Treatment of localised PCa following kidney transplantation is challenging due the presence of the kidney graft in the pelvic cavity close to the prostate. Two systematic reviews reported that oncological outcomes following PCa treatment in kidney transplant recipients are comparable to the non-transplanted population [228, 229] and surgery (radical prostatectomy), carried out in tertiary high-volume referral centres was the treatment choice in 75 to 85% of patients [228, 229]. Marra et al. reported cancer-specific survival rates of 96.8% for surgery, 88.2% for radiotherapy with androgen deprivation therapy and 100% for brachytherapy at mean follow-up of 24 months [229]. Hevia et al. reported five year cancer-specific survival of 97.5% for surgery, 87.5% for external beam radiation and 94.4% for brachytherapy [228]. Summary of evidence Surgery (radical prostatectomy) was the most frequently performed treatment for localised PCa after kidney transplant. Overall oncological outcomes following PCa treatment in kidney transplant recipients were comparable to the non-transplanted population.

Recommendations Be aware of the presence of a kidney transplant in the pelvis and the possibility of subsequent transplants when planning treatment for prostate cancer. Refer kidney transplant patients with prostate cancer to an integrated transplant urology centre.

LE 2b 2b

Strength rating Strong Strong

3.1.9 Matching of donors and recipients Histocompatibility antigens show remarkable polymorphism and human leukocyte antigen (HLA) matching is still very important in kidney transplantation as transplant outcome correlates with the number of HLA mismatches [230-233]. Human leukocyte antigen incompatibility can result in proliferation and activation of the recipient’s CD4+ and CD8+ T-cells with concomitant activation of B-cell allo-antibody production. This may lead to cellular and humoral graft rejection. Matching should concentrate on HLA antigens, which impact outcome. Human leukocyte antigens A, B, C as well as DR must be determined in all potential recipients and donors according to current guidelines and national allocation rules [230-235]. Additionally, it is recommended to determine HLA-DQ antigens of donor and recipient. Furthermore, HLA-DP antigen characterisation may be performed, especially for sensitised recipients [230-235]. All patients registered for renal transplantation must have their serum screened for anti-HLA antibodies, which are particularly common after pregnancy, previous transplant, transplant rejection, and blood transfusions [230-235]. Thorough pre-transplant testing for HLA antibodies must be performed according to current recommendations [230-235]. Sera from potential organ recipients should be screened for HLA-specific antibodies every three months or as stipulated by the national and/or international organ exchange organisations [230-235]. In addition, screening for HLA-specific antibodies should be carried out at two and four weeks after every immunising event, e.g. blood transfusion, transplantation, pregnancy, and graft explantation [230-235]. Highly sensitised patients should have prioritised access to special allocation programmes [232, 233, 235], such as the acceptable mismatch (AM) programme of Eurotransplant [236]. A careful analysis of HLA antibody specificities must be carried out to avoid unacceptable HLA antigens and to determine acceptable HLA antigens in potential donors, who are expected to give a negative cross-match result. The definition of unacceptable HLA antigens should be implemented according to local allocation rules and international recommendations [230-234, 237]. The information on unacceptable HLA antigens should be highlighted with the patient’s details in the database of the national kidney-sharing programme, preventing the unnecessary transport of kidneys to recipients with high antibody sensitivity. To avoid hyper-acute rejection (HAR), adequate (e.g. CDC, virtual) cross-match tests must be performed before each kidney and combined kidney/pancreas transplantation in accordance with national and international recommendations [230-233, 235].

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Laboratories which provide HLA-testing, HLA antibody testing and cross-matching for transplant centres must have valid accreditation to ensure accuracy and reliability [224, 225, 230-232]. They must follow the standards of national and international organisations, such as the European Federation for Immunogenetics [235]. Previously, compatibility for ABO blood group antigens and HLA antigens was of critical importance in kidney transplantation. This may change in the future, e.g. in the new U.S. allocation system A2 and A2B donors are transplanted into B recipients [233]. To avoid an increasing imbalance between demand and supply in deceased donor kidney transplantation in O recipients, ABO identity is demanded by several organ allocation organisations with a few exceptions, e.g. as in zero HLA-A+B+DR-mismatch kidneys [233, 234]. With the introduction of antibody elimination methods, potent immunosuppression and novel agents (e.g. anti B-cell drugs), successful ABO-incompatible living donor transplantations, with good long-term outcomes are possible [238, 239]. However, higher costs and infection rates have been described. Even the barrier of a positive cross-match due to preformed HLA antibodies is under discussion with newer “desensitisation” techniques available in cases with available living donors [240, 241]. Success rates are lower, antibody-mediated rejections are frequent, but survival may be better compared to waiting list survival on dialysis. While this is a rapidly evolving field, further research is needed to define standard protocols. Until then such “desensitisation” protocols are experimental and patients undergoing “desensitisation” should be treated in specialised centres, where outcomes are documented. Patients should be informed adequately of the risks and limitations and alternative strategies (e.g. acceptable mismatch programmes, cross-over transplantation and donor chains) should be discussed. Summary of evidence LE Human leukocyte antigen matching is very important in kidney transplantation as transplant outcome 3 correlates with the number of HLA mismatches. Matching should concentrate on HLA antigens, which impact outcome. 3 In accordance with national and international recommendations adequate (e.g. CDC, virtual) crossmatch tests must be performed before each kidney and combined kidney/pancreas transplantation to avoid hyper-acute rejection.

Recommendations Determine the ABO blood group and the human leukocyte antigen A, B, C and DR phenotypes for all candidates awaiting kidney transplantation. Test both the donor and recipient for human leukocyte antigen DQ. Human leukocyte antigen DP testing may be performed for sensitised patients. Perform thorough testing for HLA antibodies before transplantation. Perform adequate cross-match tests to avoid hyper-acute rejection, before each kidney and combined kidney/pancreas transplantation.

Strength rating Strong Strong Strong Strong

3.1.10 Immunosuppression after kidney transplantation The principle underlying successful immunosuppression is ‘the balance of survival’. Practitioners must prescribe a dosage of drug high enough to suppress rejection without endangering the recipient’s health. Increased understanding of immune rejection has led to the development of safe modern immune suppression agents [242, 243], which suppress sensitised lymphocyte activity against a transplant. Immunosuppression is particularly important during the initial post-transplant period when there is a high incidence of early posttransplant rejection. In later post-operative stages, ‘graft adaptation‘ occurs, resulting in the very low rejection rates seen in maintenance patients. Rejection prophylaxis should therefore be reduced over time by steroid tapering and gradual lowering of calcineurin inhibitor (CNI) [242-244]. Non-specific side effects of immunosuppression include a higher risk of malignancy and infection, particularly opportunistic infections [242-244]. All immunosuppressants also have dose-dependent specific side effects. Current immunosuppressive protocols aim to reduce drug-specific side effects using a synergistic regimen. A truly synergistic regimen allows profound dose reductions of immunosuppressive drugs; therefore, reducing side effects whilst still maintaining efficacy due to the synergistic effects of the immunosuppressants. The currently recommended standard initial immunosuppression regime provides excellent efficacy with good tolerability [242-245]. It is given to most patients and consists of:

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• • • •

calcineurin inhibitors (preferably tacrolimus, alternatively cyclosporine); mycophenolate (MMF or enteric-coated mycophenolate sodium [EC-MPS]); steroids (prednisolone or methylprednisolone); induction therapy (preferably basiliximab in low and standard risk patients and anti-thymocyte globulin [ATG] in high-risk patients).

This multidrug regimen reflects the current standard of care for the majority of transplant recipients worldwide [242-244] and may be modified according to local needs and immunological risk. This standard regimen is likely to change as new immunosuppressive drugs and new treatment regimens are developed [242-244]. In addition, any initial drug regimen will need to be tailored to the individual needs of a patient as suggested by the appearance of side effects, lack of efficacy or protocol-driven requirements. Recommendation Perform initial rejection prophylaxis with a combination therapy of a calcineurin inhibitor (preferably tacrolimus), mycophenolate, steroids and an induction agent (either basiliximab or anti-thymocyte globulin).

Strength rating Strong

3.1.10.1 Calcineurin inhibitors Both cyclosporine and tacrolimus have significant side effects that are hazardous to the graft and patient [242249]. Most importantly, both are nephrotoxic [250, 251], and long-term use is an important cause of chronic allograft dysfunction [252], eventually leading to graft loss or severe chronic kidney disease in recipients of non-renal organs. Both CNIs are considered to be ‘critical-dose’ drugs, so that any deviations from exposure can lead to severe toxicity or failure of efficacy. Due to their narrow therapeutic window and the potential for drug-to-drug interaction, CNIs should be monitored using trough levels, which provide a reasonable estimate for exposure [249]. Meta-analysis of tacrolimus and cyclosporine has demonstrated similar outcomes with respect to overall patient and graft survival [242-248, 253, 254]. Tacrolimus provided better rejection prophylaxis and was associated with better graft survival, when censored for death in some analyses. Renal function was favourable for tacrolimus treated patients, in a number of trials [254-259]. Therefore, both CNIs can be used for the effective prevention of acute rejection, but due to higher efficacy tacrolimus is recommended by current guidelines as first-line CNI [243]. For both CNIs several different formulations are available [249, 260-268]. Tacrolimus once-daily dosing seems to be preferred by patients and is associated with better adherence and lower pharmacokinetic variability [249, 269, 270]. Precautions (e.g. close surveillance and determination of drug levels) should be instituted after conversion from one formulation to another [268, 271-275]. In case of specific side effects of a CNI (e.g. hirsutism, alopecia, gingival hyperplasia, diabetes, polyoma nephropathy) conversion to another CNI can be a successful strategy to reduce side effects [242-244, 276]. Due to differences in the efficacy and safety profile, the choice of CNI should include the individual risks and benefits for each patient. Despite their side effects, CNIs have been a cornerstone of modern immunosuppressive regimens for more than thirty years as they have resulted in an exemplary improvement in kidney graft survival [242, 243]. Future protocols aim to minimise or even eliminate CNIs [244, 247, 249, 277-280]. However, until such strategies provide superior outcomes, CNIs remain the standard of care [242, 243, 281]. For severe CNI-related side effects, CNI withdrawal, replacement, or profound reduction may be needed [242, 244, 247, 277, 278]. Special attention should be paid to maintenance patients, who may need less CNIs than previously thought [242, 244, 249, 278, 279, 282]. Summary of evidence Meta-analysis of tacrolimus and cyclosporine has demonstrated similar outcomes with respect to overall patient and graft survival; however, tacrolimus provided better rejection prophylaxis. Due to differences in the efficacy and safety profile, the choice of CNI should take into account the immunological risk, characteristics, concomitant immunosuppression, and socio-economic factors of the recipient.

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Recommendations Use calcineurin inhibitors for rejection prophylaxis as they represent current best practice pending publication of long-term results using newer agents. Use tacrolimus as first-line calcineurin inhibitor due to its higher efficacy. Monitor blood-levels of both cyclosporine and tacrolimus to allow appropriate dose adjustment of calcineurin inhibitors.

Strength rating Strong Strong Strong

3.1.10.2 Mycophenolates (MPA) The mycophenolates, MMF and EC-MPS, are based on mycophenolic acid, which inhibits inosine monophosphate dehydrogenase (IMPDH) [283-287]. This is the rate-limiting step for the synthesis of guanosine monophosphate in the de novo purine pathway. As the function and proliferation of lymphocytes is more dependent on de novo purine nucleotide synthesis compared to other cell types, IMPDH inhibitors may provide more specific lymphocyte-targeted immunosuppression. The co-administration of MPA with prednisolone and CNI has resulted in a profound reduction of biopsy-proven rejections [242, 245, 283-287]. Mycophenolic acid is not nephrotoxic; however, it inhibits bone marrow function and may cause CMV infections and gastrointestinal side effects, particularly diarrhoea [242, 245, 283-287]. There is also a higher incidence of polyoma nephropathy, especially when mycophenolate is combined with tacrolimus [288]. Both MPA formulations are equally effective with an almost identical safety profile [240, 278, 281, 283-286], though some prospective studies suggest a better gastrointestinal side-effect profile for EC-MPS in patients who have suffered from MMF-related gastrointestinal complaints, although firm evidence from prospective randomised studies is lacking [283-287, 289]. Mycophenolic acid is recommended by guidelines [243]. Standard doses in combination with cyclosporine are MMF 1 g or EC-MPS 720 mg twice daily, although higher initial doses have been suggested [242, 243, 283-287]. Despite its frequent use with tacrolimus, there is insufficient evidence to support the optimal dosage for this combination [242, 283, 285, 286, 290]. Tacrolimus has no influence on MPA exposure and leads to approximately 30% higher MPA exposure compared to cyclosporine. Most transplant centres use the same starting dose as in cyclosporine-treated patients, however dose reductions are frequent, especially because of gastrointestinal side effects. Weak evidence suggests that MPA dose reductions are associated with inferior outcomes, especially in cyclosporine treated patients [284-286, 291, 292]. Due to the high incidence of side effects, some centres perform a protocol-driven MPA dose reduction in tacrolimus treated patients [283, 285]. Regular monitoring for polyoma (BK virus) is recommended in patients given MPA combined with tacrolimus [242, 288]. Due to a higher incidence of CMV disease with MPA [287], either CMV prophylaxis or a pre-emptive strategy with regular screening for CMV viraemia should be instituted [242, 293]. Cytomegalovirus prophylaxis with antiviral medications (e.g. valganciclovir) should be used routinely in CMV positive recipients and in CMV negative recipients of CMV positive organ transplants, because prophylaxis has recently been shown to reduce CMV disease, CMV-associated mortality in solid organ transplant recipients, and leads to better long-term graft survival in kidney allograft recipients. The benefit for MPA drug monitoring is uncertain and currently not recommended for the majority of patients [283, 285, 286, 294]. In maintenance patients, the potency of MPA can be used for successful steroid withdrawal in most patients [295] or for substantial dose reductions of nephrotoxic CNIs, which may lead to better renal function [242-245, 247, 278, 296]. Although there have been several studies of the potential for CNI-free protocols with MPA and steroids, complete CNI avoidance or withdrawal over the first three years has been associated with a substantially increased rejection risk and even worse outcomes in prospective randomised studies [242, 244, 278]. In contrast, CNI withdrawal under MPA and steroids appeared to be safe in long-term maintenance patients beyond five years post-transplant and resulted in improved renal function [242, 244, 247, 278, 296, 297]. Summary of evidence The co-administration of MPA with prednisolone and CNI has resulted in a profound reduction of biopsy-proven rejections. Both MPA formulations, MMF and EC-MPS, are equally effective with an almost identical safety profile. Due to a higher incidence of CMV disease with MPA either CMV prophylaxis or a pre-emptive strategy with regular screening for CMV viraemia should be instituted.

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Recommendation Administer mycophenolate as part of the initial immunosuppressive regimen.

Strength rating Strong

3.1.10.3 Azathioprine Mycophenolate is now routinely used as a primary therapy in place of azathioprine in most units worldwide. In comparison to azathioprine, MPA reduced rejection rates significantly in prospective randomised trials [242, 243, 245, 283-287]. Although a large, prospective study found that azathioprine may give acceptable results in a low-risk population [298], azathioprine is usually reserved for patients who cannot tolerate MPA [242, 243, 283, 284, 286]. When added to dual therapy with cyclosporine and steroids, a meta-analysis found no significant benefit for azathioprine with respect to major outcome parameters [299]. Recommendation Azathioprine may be used in a low-risk population as an immunosuppressive drug, especially for those intolerant to mycophenolate formulations.

Strength rating Weak

3.1.10.4 Steroids Steroids have a large number of side effects [242-244, 295], especially with long-term use. Most practitioners still consider steroids (either prednisolone or methylprednisolone) to be a fundamental adjunct to primary immunosuppression, even though successful steroid withdrawal has been achieved in the vast majority of patients in many prospective, randomised trials [242, 244, 245, 295, 300, 301]. The risk of steroid withdrawal depends on the use of concomitant immunosuppressive medication, immunological risk, ethnicity, and time after transplantation. Although the risk of rejection diminishes over time, potential benefits may be less prominent after a prolonged steroid treatment period [242-245, 295]. Recent studies suggest similar efficacy but less diabetes after early steroid withdrawal or steroid minimisation in low-risk patients treated with tacrolimus, MPA and induction (either basiliximab or ATG) [302, 303]. Recommendations Strength rating Initial steroid therapy should be part of immunosuppression in the peri-operative and early Strong post-transplant period. Consider steroid withdrawal in standard immunological risk patients on combination therapy Weak with calcineurin inhibitors and mycophenolic acid after the early post-transplant period. 3.1.10.5 Inhibitors of the mammalian target of rapamycin (m-TOR) The immunosuppressants, sirolimus and everolimus, inhibit the mammalian target of rapamycin and suppress lymphocyte proliferation and differentiation [242, 277, 304-306]. They inhibit multiple intracellular pathways and block cytokine signals for T-cell proliferation. Similar effects are seen on B-cells, endothelial cells, fibroblasts, and tumour cells. Inhibitors of m-TOR are as effective as MPA when combined with CNIs in preventing rejection [242, 245, 277, 304-307]. However, m-TOR inhibitors exhibit dose-dependent bone marrow toxicity [242, 277, 304-306]. Other potential side effects include hyperlipidaemia, oedema, development of lymphoceles, wound healing problems, pneumonitis, proteinuria, and impaired fertility. The extensive side effect profile is responsible for inferior tolerability compared to MPA and potential differences in outcome in early years, when higher doses were used [308-313]. To date, no prospective comparative studies have been carried out on the m-TOR inhibitors sirolimus and everolimus [314]. Both m-TOR inhibitors have an almost identical side effect profile and mainly differ in their pharmacokinetic properties [242, 277, 304-306, 315]. Sirolimus has a half-life of about 60 hours, is given once a day and is licensed for prophylaxis in kidney recipients only. Everolimus has a half-life of about 24 hours, is licensed for kidney, liver and heart recipients and is given twice a day. Everolimus is licenced for use with cyclosporine and can be given simultaneously with cyclosporine, while sirolimus should be given four hours after cyclosporine. The pharmacological drug-drug interaction with cyclosporine is far less relevant for tacrolimus, resulting in the need for a higher starting dose of m-TOR inhibitors in combination with tacrolimus [258, 316, 317]. Sirolimus is also licensed in combination therapy with steroids for cyclosporine withdrawal from combination therapy with cyclosporine. Therapeutic monitoring of trough levels is recommended because of the narrow therapeutic window and the risk of drug-to-drug interactions [242, 277, 304-306, 315].

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When combined with CNIs, antimicrobial prophylaxis for Pneumocystis jirovecii pneumonia should be administered for one year following transplantation, e.g. low-dose cotrimoxazole [242, 304-306]. Most importantly, combination therapy with CNIs aggravates CNI-induced nephrotoxicity, although m-TOR inhibitors themselves are non-nephrotoxic [242]. Several studies suggest less favourable outcomes and increased drug discontinuations due to adverse events for this combination, especially if CNIs are maintained at standard dosages [242, 245, 247, 258, 307, 309, 310, 318-323]. Calcineurin inhibitor dosage should therefore be substantially reduced in combination therapy with m-TOR inhibitors, which seems to have no impact on efficacy, due to the highly synergistic potential of this combination therapy [277, 304-306, 312, 315]. Several studies suggest m-TOR inhibitors cannot replace CNIs in the initial phase after transplantation due to lower efficacy and a less favourable side effect profile, particularly wound healing problems and lymphoceles [240, 242, 243, 274, 298, 299, 304, 306, 314]. Other trials suggest that m-TOR inhibitors may replace CNI at later stages, e.g. three months after transplantation, with improvements in renal function, predominately in cyclosporine treated patients [242, 244, 245, 247, 256, 277, 304-306, 309, 310, 312, 324-326]. It is unclear if there is a real benefit in comparison to patients on tacrolimus and MPA [256, 325]. However, there is an increased risk of rejection and development of HLA antibodies [242, 244, 256, 277, 327], which may be offset by the benefit of the non-nephrotoxic immunosuppression. Patients treated with m-TOR inhibitors develop less leucopenia and opportunistic viral infections, especially less CMV infections compared to MPA [258, 309, 312, 322-324, 328]. Proteinuria and poor renal function at conversion are associated with inferior outcomes [242, 244, 277, 304306]. Conversion from CNIs is not advisable in patients with proteinuria > 800 mg/day, and a cautious and individual approach should be followed in patients with GFR < 30 mL/min. Due to an anti-proliferative effect and a lower incidence of malignancy in m-TOR inhibitor treated patients, conversion from CNIs to m-TOR inhibitors may be beneficial for patients, who develop malignancy after transplantation, or who are at a high risk for the development of post-transplant malignancy or skin cancer [242, 244, 277, 304-306, 311-313, 329-332]. Several studies and case reports have suggested that patients with Kaposi sarcoma under CNI therapy benefit from conversion to an m-TOR inhibitor [330]. In summary, m-TOR inhibitors are not recommended as initial immunosuppressive therapy due to their side effect profile and higher discontinuation rates [243]. However, m-TOR inhibitors are a well-studied alternative treatment option. Summary of evidence Combination therapy with CNIs aggravates CNI-induced nephrotoxicity. Therefore, CNI dosage should be substantially reduced in combination therapy with m-TOR inhibitors, which seems to have no impact on efficacy, due to the highly synergistic potential of this combination therapy. Take into consideration impaired wound healing and prophylactic surgical measures when m-TOR inhibitors are used as part of the initial immunosuppressive regimen or when patients treated with m-TOR inhibitors undergo major surgery. When combined with CNIs, antimicrobial prophylaxis for P. jirovecii pneumonia should be administered for one year following transplantation. Conversion from CNIs is not advisable in patients with proteinuria > 800 mg/day, and a cautious and individual approach should be followed in patients with GFR < 30 mL/min. Recommendations The m-TOR inhibitors may be used to prevent rejection in patients who are intolerant to standard therapy. Significantly reduce calcineurin inhibitor dosage in a combination regimen with m-TOR inhibitors to prevent aggravated nephrotoxicity. Do not convert patients with proteinuria and poor renal function to m-TOR inhibitors. Monitor blood-levels of both sirolimus and everolimus to allow for appropriate dose adjustment.

LE 1

1

1 1

Strength rating Weak Strong Strong Strong

3.1.10.6 Induction with Interleukin-2 receptor antibodies Basiliximab, a high-affinity anti-interleukin-2 (IL-2) receptor monoclonal antibody is approved for rejection prophylaxis following organ transplantation [242, 243, 245, 333-337]. Basiliximab is given before

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transplantation and on day four post-transplant. The drug is safe, and IL-2 receptor antibodies have been shown in RCTs to reduce the prevalence of acute cellular rejection by approximately 40% [242, 243, 245, 333-335]. Meta-analyses [245, 333-335] have confirmed the efficacy, although no positive effect on patient or graft survival could be demonstrated, large retrospective cohort studies and recent large prospective studies suggest such a benefit [242, 243, 338, 339]. Several large controlled trials support the efficacy and safety of quadruple therapy with tacrolimus, mycophenolate and steroids. Interleukin-2 receptor antibodies may allow early steroid withdrawal [295], although higher rejection rates were described in some studies. Most importantly, IL-2 receptor antibodies allow a substantial reduction in CNIs or steroids, while maintaining excellent efficacy and renal function [242-245, 302, 333-335]. Therefore, this regimen is proposed as first-line immunosuppression in patients with low to normal immunological risk [243, 339]. Recommendation Use interleukin-2 receptor antibodies for induction in patients with normal immunological risk in order to reduce incidence of acute rejection.

Strength rating Weak

3.1.10.7 T-cell depleting induction therapy Prophylactic immunosuppression regimens in many countries, particularly the U.S., use potent T-cell depleting ‘induction’ treatments [242, 243, 245, 333, 338, 340-343]. Most frequently, ATG is used for prevention of rejection in immunological high-risk patients, as supported by meta-analysis [339], and recommended by guidelines [243, 344]. In addition, these potent biological agents are used for the treatment of severe, steroid resistant rejection episodes [340, 343]. Use of T-cell depleting antibodies in immunological low-risk patients has not been associated with improved long-term outcomes but with an increased risk of severe opportunistic infections and malignancy, particularly post-transplant lymphoproliferative disease [242, 243, 245, 333, 339-341]. Some centres use these agents to provide effective rejection prophylaxis in order to facilitate steroid withdrawal [302, 338, 342]. Recommendation T-cell depleting antibodies may be used for induction therapy in immunologically high-risk patients.

Strength rating Weak

3.1.10.8 Belatacept Belatacept is a fusion protein, which effectively blocks the CD28 co-stimulatory pathway and thereby prevents T-cell activation [277, 345, 346]. Belatacept is intravenously administered and indicated for use as part of a CNI-free regimen together with basiliximab induction, MPA, and corticosteroids. Long-term data from three randomised studies of de novo kidney transplant recipients demonstrated better renal function vs. cyclosporine-based immunosuppression, although rates and grades of acute rejection were higher for belatacept in the first year post-transplant [242, 245, 257, 277, 345-351]. In patients receiving a standard deceased or living donor kidney, better graft survival was observed, while similar graft survival rates were found with ECDs. Interestingly, belatacept-treated patients had better preserved histology and developed less donor specific antibodies (DSA) compared to cyclosporine [352]. The long-term safety profile of belatacept treated patients was similar to cyclosporine controls, less belatacept treated patients developed metabolic complications or discontinued treatment due to adverse events [350, 351, 353, 354]. In addition, the option of converting patients (either stable patients or due to CNI or m-TOR associated toxicity) was explored with promising initial results [348, 355-357]. Specific safety signals include a higher rate of post-transplant lymphoproliferative disorder (especially in Epstein-Barr virus (EBV) negative patients), more herpes infections, and tuberculosis in patients from endemic areas [277, 345, 346]. Belatacept was approved in the U.S. and in Europe for EBV positive patients, but is not yet available in many countries. Additional studies are ongoing to fully explore the value of this compound. Recommendation Belatacept may be used for immunosuppressive therapy in immunologically low-risk patients, who have a positive Epstein-Barr virus serology.

Strength rating Weak

3.1.11 Immunological complications Immunological rejection is a common cause of early and late transplant dysfunction [243, 358-362]. There is great variation in the timing and severity of rejection episodes and how they respond to treatment. Today two

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main types of immunological reactions are distinguished, T-cell mediated rejections (TCMR) and antibodymediated rejections (ABMR) [243, 358-360]. Antibody-mediated rejection and TCMR may be diagnosed together, called mixed acute rejection. Antibody-mediated rejection may occur as hyperacute rejection (HAR), active rejection or chronic rejection. Chronic ABMR is considered as one of the leading causes of late graft loss. The ultimate standard for the diagnosis of rejection is transplant biopsy [243], because it is impossible to differentiate acute rejection solely on clinical indicators from other causes of renal dysfunction (e.g. acute tubular necrosis, infection, disease recurrence or CNI nephrotoxicity). Therefore, all rejections should be verified by renal biopsy and biopsies should be classified according to the most recent Banff criteria [363], which are the basis for prognosis and treatment [241, 358, 361]. Renal transplant biopsy should be conducted preferably under US control, using an automated needle biopsy system (e.g. Tru-Cut biopsy gun) [243, 358] with a 16 G needle to assure specimen adequacy. The biopsy procedure is considered safe but complications such as bleeding and AV fistulas may occur [243, 364, 365]. The reported risk of major complications (including substantial bleeding, macroscopic haematuria with ureteric obstruction, peritonitis or graft loss) is approximately 1%. Most important contraindications are anti-coagulant therapy including anti-platelet agents and uncontrolled hypertension. Summary of evidence There must be routine access to US-guided biopsy of the transplant and sufficient expertise in the hospital pathology department to allow a rapid and clear-cut diagnosis of rejection or other type of allograft dysfunction. Steroid treatment for rejection may start before the renal biopsy is performed.

Recommendations Monitor transplant recipients for signs of acute rejection, particularly during the first six months post-transplant. Take regular blood samples in addition to regular monitoring of urine output and ultrasound examinations in order to detect graft dysfunction during hospitalisation. Immediately rule out other potential causes of graft dysfunction in cases of suspected acute rejection. An ultrasound of the kidney transplant should be performed. Perform a renal biopsy, graded according to the most recent Banff criteria, in patients with suspected acute rejection episodes. Only if contraindications to renal biopsy are present, can ‘blind’ steroid bolus therapy be given. Test patients who suffer acute rejection as soon as possible for anti-HLA antibodies against the graft. Reassess the immunosuppressive therapy of all patients with rejection, including patient adherence to the medication, which is of particular importance in late rejections.

LE 2

2

Strength rating Strong Strong Strong Strong Strong Strong Strong

3.1.11.1 Hyper-acute rejection Hyper-acute rejection is the most dramatic and destructive immunological attack on the graft [230, 243, 358, 359]. It results from circulating, complement-fixing IgG antibodies, specifically reactive against incompatible donor antigen, which engages with and destroys the vascular endothelium within minutes or hours after vascularisation. It occurs in ABO-incompatible grafts due to the presence of high titres of pre-existing isoantibodies against blood group antigens. In ABO-matched grafts, HAR is mediated by anti-donor HLA IgG antibodies. With the development of the cross-match test before transplantation, HAR has become an extremely uncommon complication [230]. Imaging and histology reveals generalised infarction of the graft, which has to be treated by graft nephrectomy. Therefore, prevention is crucial, either by avoidance of high isoantibodies against incompatible blood group antigens in case of an ABO-incompatible renal transplant and/or by performing a regular cross-match before transplantation (see section 3.1.9). Recommendation Prevent hyper-acute rejection by adequate ABO blood group and HLA matching of donor and recipients.

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3.1.11.2 Treatment of T-cell mediated acute rejection As only a few randomised trials have investigated different treatment options for this clinical problem, therapy is mainly based on empirical experience rather than on clinical evidence [243, 343, 358, 366]. Parenteral methylprednisolone (500 mg to 1 g) should be given intravenously as one pulse per day for three days. Anuria or a steep rise in the serum creatinine may indicate steroid-refractory rejection and the need for another three day course of pulsed methylprednisolone therapy [243, 358]. In addition, baseline immunosuppression should be optimised to ensure adequate drug exposure [243, 358, 366]. In severe rejection, a conversion from cyclosporine to tacrolimus and/or from azathioprine to MPA is recommended [243, 358]. T-cell depleting biological agents, such as ATG may be given in severe steroid-refractory cases [243, 340, 343, 358, 366]. If biological agents are used, other immunological suppression should be adapted and daily T-cell monitoring should be considered to minimise the dose of the biological agent [340]. Before immunosuppression is intensified, especially before the use of T-cell depleting agents, the prognosis of the graft should be critically assessed against the risks of the aggravated immunosuppression. The patient should be counselled adequately. Recommendations Use steroid bolus therapy as first-line treatment for T-cell mediated rejection in addition to ensuring adequate baseline immunosuppression. In severe or steroid-resistant rejection, use intensified immunosuppression, high-dose steroid treatment, and eventually T-cell depleting agents.

Strength rating Strong Strong

3.1.11.3 Treatment of antibody mediated rejection (ABMR) Treatment of ABMR relies mainly on retrospective studies and empirical treatment guidelines [367]. Consensus is that it is important to classify the clinical and histological phenotype of the rejection in order to make adequate treatment decisions [367]. Important clinical factors are time of rejection (early acute < 30 days post-transplant vs. late), preformed vs. de novo donor-specific antibodies (DSA), and histology (active vs. chronic rejection). For active ABMR due to pre-existing DSA treatment with a steroid bolus (at least three days of 500 mg/day) in combination with intravenous immunoglobulin (IVIG) and plasmapheresis or immune-adsorption is recommended. Intravenous immunoglobulin (IVIG) [243, 358, 368-373] may modulate and/or suppress antibody production. Intravenous immunoglobulin alone seems insufficient for effective treatment and IVIG is used today in a multimodal regimen. Dosages vary widely from 0.2-2.0 g/kg bodyweight, and no comparative studies (e.g. on the dose or optimal concomitant immunosuppression) have been published. Retrospective and prospective case series clearly suggest efficacy of antibody removal using plasmapheresis or immune-adsorption columns [243, 358, 368-373], although details of the procedures vary widely. Adjunctive therapies such as complement inhibitors, rituximab or splenectomy might be considered in severe early acute cases. Despite controversial data on the utility of anti-CD20 antibody [243, 343, 358, 368-373], rituximab may also be considered as adjunctive therapy in late active ABMR according to expert consensus. Although T-cell depleting agents such as ATG appear to have limited value they are frequently used during mixed acute rejection [241]. However, retrospective series suggests aggravated toxicity, when rituximab is combined with ATG [374], or steroids [343]. Furthermore, many centres will optimise maintenance therapy with MPA and steroids and sufficient tacrolimus trough levels should be achieved [243, 358, 368-370, 373]. Chronic acute mixed rejection due to pre-existent DSA has no specific treatment recommendations except for optimisation of maintenance therapy and eventually IVIG as an adjunctive treatment with a low level of evidence. In patients presenting with de novo DSA optimisation of maintenance, immunosuppression is recommended and non-adherence should be addressed and managed accordingly. If histology shows active ABMR plasmapheresis, rituximab and IVIG can be considered as potential adjunctive agents without good evidence from clinical trials. If biopsy demonstrates pure chronic ABMR no special treatment is recommended due to lack of convincing data, except for IVIG as potential treatment option without firm evidence. Treatment for chronic ABMR appears to be less successful [358, 368, 370]. In summary, several regimens have proven some efficacy in ABMR. However, except for a beneficial effect of early antibody removal, the lack of firm evidence does not permit evidence-based recommendations for treatment. As a consequence, prevention of ABMR by adequate pre-transplant screening, regular DSA monitoring, avoidance of suboptimal immunosuppression and reinforcement of adherence are crucial [230, 358, 372, 375].

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Recommendation Treatment of antibody mediated rejection should include antibody elimination.

Strength rating Strong

3.1.12 Follow-up after transplantation Long-term graft function is of critical importance for the success of a transplant [243, 244]. Therefore, regular long-term follow-up by experienced transplant physicians is essential in order to detect complications or graft dysfunction early and reassure adherence to the immunosuppressive regimen. Complications of immunosuppression occur frequently including specific complications of the different drugs as well as over immunosuppression (namely opportunistic infections and malignancy) [243, 244]. The risk of cancer and cardiac disease is several-fold higher in transplanted patients than in the general population. Cancer is a cause of significant morbidity and mortality in the transplanted population [243, 376, 377]. Cardiovascular disease is the most frequent cause of death in renal allograft recipients [243, 378, 379]. Other important long-term problems are non-adherence, the development of anti-HLA antibodies, recurrence of the original disease and CNI associated nephrotoxicity [243, 244]. 3.1.12.1 Chronic allograft dysfunction/interstitial fibrosis and tubular atrophy Many patients lose their grafts due to chronic allograft dysfunction [243, 244, 380]. Histology will usually reveal a chronic process of interstitial fibrosis and tubular atrophy (IF/TA) [381]. Some patients will have immunological chronic ABMR [382], as discussed in section 3.1.11.3. Interstitial fibrosis and tubular atrophy takes months or years to develop and is heralded by proteinuria and hypertension, with a simultaneous or delayed rise in serum creatinine level over months [243, 380, 381]. It is likely that IF/TA is more common in patients who have had early attacks of acute rejection or infection. The main differential diagnosis is chronic nephrotoxicity [383], which is common in patients receiving CNIs, and pre-existing and/or aggravated chronic kidney damage from a marginal donor kidney [243, 380, 381]. Diagnosis is by renal biopsy [243, 380]. In patients diagnosed early, particularly if there is evidence for CNI toxicity, disease progression may be slowed by conversion to a CNI-free regimen [201-203, 263, 264]. Conversion to m-TOR inhibitors is an option for patients without significant proteinuria (< 800 mg/day), but moderate renal function [242-244]. Alternatively, successful conversion to a mycophenolate based regimen has been described, especially in patients beyond the first three years post-transplant [242, 244, 278]. If there is intolerance to m-TOR inhibitors or MPA, conversion to belatacept or an azathioprine-based regimen may be successful, though the higher risk of rejection warrants close surveillance [357]. If the risk of rejection seems too high, another option is substantial reduction of CNI under the protection of MPA [244, 278]. In patients with proteinuria, intervention with an angiotensin converting enzyme inhibitor, or angiotensin II receptor blocker [243, 380] together with tight blood pressure control may slow down renal progression. Other supportive measures include the treatment of hypertension, hyperlipidaemia, diabetes, anaemia, acidosis, and bone disease [243]. However, ultimately, the patient will require another transplant (if fit enough to go on the transplant waiting list) or dialysis therapy. Summary of evidence Regular long-term follow-up by experienced transplant physicians is essential in order to detect complications or graft dysfunction early and reassure adherence to the immunosuppressive regimen. Annual screening should include a dermatological examination, cardiovascular history and exam, tumour screening (including a nodal examination, faecal occult screening, chest x-ray, gynaecological and urological examination), and an abdominal US, including US of the native and transplanted kidney. If appropriate, further diagnostic tests should be prompted to treat or slow down the progression of any identified complication. In patients diagnosed early with IF/TA, particularly if there is evidence for CNI toxicity, disease progression may be slowed by conversion to a CNI-free regimen. If the risk of rejection seems too high, another option is substantial reduction of CNI under the protection of MPA. Supportive measures should aim to adequately treat the consequences of chronic kidney disease (e.g. anaemia, acidosis, bone disease). Recommendations Provide lifelong regular post-transplant follow-up by an experienced and trained transplant specialist at least every six to twelve months. Advise patients on appropriate lifestyle changes, potential complications, and the importance of adherence to their immunosuppressive regimen.

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Regularly monitor (approximately every four to eight weeks) serum creatinine, estimated glomerular filtration rate, blood pressure, urinary protein excretion, immunosuppression and complications after renal transplantation. Changes in these parameters over time should trigger further diagnostic work-up including renal biopsy, a search for infectious causes and anti-HLA antibodies. Perform an ultrasound of the graft, in case of graft dysfunction, to rule out obstruction and renal artery stenosis. In patients with interstitial fibrosis and tubular atrophy undergoing calcineurin inhibitor (CNI) therapy and/or with histological signs suggestive for CNI toxicity (e.g. arteriolar hyalinosis, striped fibrosis) consider CNI reduction or withdrawal. Initiate appropriate medical treatment, e.g. tight control of hypertension, diabetes, proteinuria, cardiac risk factors, infections, and other complications according to current guidelines.

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Douketis, J.D., et al. Perioperative Management of Antithrombotic Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 2012. 141. https://pubmed.ncbi.nlm.nih.gov/22315266 Benahmed, A., et al. Ticlopidine and clopidogrel, sometimes combined with aspirin, only minimally increase the surgical risk in renal transplantation: A case-control study. Nephrol Dial Transplant, 2014. 29: 463. https://pubmed.ncbi.nlm.nih.gov/24275542 Osman, Y., et al. Necessity of Routine Postoperative Heparinization in Non-Risky Live-Donor Renal Transplantation: Results of a Prospective Randomized Trial. Urology, 2007. 69: 647. https://pubmed.ncbi.nlm.nih.gov/17445644 Orlando, G., et al. One-shot versus multidose perioperative antibiotic prophylaxis after kidney transplantation: a randomized, controlled clinical trial. Surgery, 2015. 157: 104. https://pubmed.ncbi.nlm.nih.gov/25304836 Choi, S.U., et al. Clinical significance of prophylactic antibiotics in renal transplantation. Transplant Proc, 2013. 45: 1392. https://pubmed.ncbi.nlm.nih.gov/23726580 O’Malley, C.M., et al. A randomized, double-blind comparison of lactated Ringer’s solution and 0.9% NaCl during renal transplantation. Anesth Analg, 2005. 100: 1518. https://pubmed.ncbi.nlm.nih.gov/15845718 Othman, M.M., et al. The impact of timing of maximal crystalloid hydration on early graft function during kidney transplantation. Anesth Analg, 2010. 110: 1440. https://pubmed.ncbi.nlm.nih.gov/20418304 Dalton, R.S., et al. Physiologic impact of low-dose dopamine on renal function in the early post renal transplant period. Transplantation, 2005. 79: 1561. https://pubmed.ncbi.nlm.nih.gov/15940046 Ciapetti, M., et al. Low-dose dopamine in kidney transplantation. Transplant Proc, 2009. 41: 4165. https://pubmed.ncbi.nlm.nih.gov/20005360 Hanif, F., et al. Outcome of renal transplantation with and without intra-operative diuretics. Int J Surg, 2011. 9: 460. https://pubmed.ncbi.nlm.nih.gov/21600319 Valeriani, G., et al. Bench surgery in right kidney transplantation. Transplant Proc, 2010. 42: 1120. https://pubmed.ncbi.nlm.nih.gov/20534239 Wagenaar, S., et al. Minimally Invasive, Laparoscopic, and Robotic-assisted Techniques Versus Open Techniques for Kidney Transplant Recipients: A Systematic Review. Eur Urol, 2017. 72: 205. https://pubmed.ncbi.nlm.nih.gov/28262412 Chedid, M.F., et al. Living donor kidney transplantation using laparoscopically procured multiple renal artery kidneys and right kidneys. J Am Coll Surg, 2013. 217: 144. https://pubmed.ncbi.nlm.nih.gov/23791283 Kaminska, D., et al. The influence of warm ischemia elimination on kidney injury during transplantation - clinical and molecular study. Sci Rep, 2016. 6: 36118. https://pubmed.ncbi.nlm.nih.gov/27808277 Ozdemir-van Brunschot, D.M., et al. Is the Reluctance for the Implantation of Right Donor Kidneys Justified? World J Surg, 2016. 40: 471. https://pubmed.ncbi.nlm.nih.gov/26319261 Khalil, A., et al. Trends and outcomes in right vs. left living donor nephrectomy: an analysis of the OPTN/UNOS database of donor and recipient outcomes--should we be doing more right-sided nephrectomies? Clin Transplant, 2016. 30: 145. https://pubmed.ncbi.nlm.nih.gov/26589133 Hsu, J.W., et al. Increased early graft failure in right-sided living donor nephrectomy. Transplantation, 2011. 91: 108. https://pubmed.ncbi.nlm.nih.gov/21441855 Kulkarni, S., et al. Outcomes From Right Versus Left Deceased-Donor Kidney Transplants: A US National Cohort Study. Am J Kidney Dis, 2020. 75: 725. https://pubmed.ncbi.nlm.nih.gov/31812448/ Wang, K., et al. Right Versus Left Laparoscopic Living-Donor Nephrectomy: A Meta-Analysis. Exp Clin Transplant, 2015. 13: 214. https://pubmed.ncbi.nlm.nih.gov/26086831

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Ciudin, A., et al. Transposition of iliac vessels in implantation of right living donor kidneys. Transplant Proc, 2012. 44: 2945. https://pubmed.ncbi.nlm.nih.gov/23195003 Phelan, P.J., et al. Left versus right deceased donor renal allograft outcome. Transpl Int, 2009. 22: 1159. https://pubmed.ncbi.nlm.nih.gov/19891044 Feng, J.Y., et al. Renal vein lengthening using gonadal vein reduces surgical difficulty in living-donor kidney transplantation. World J Surg, 2012. 36: 468. https://pubmed.ncbi.nlm.nih.gov/21882021 Nghiem, D.D. Use of spiral vein graft in living donor renal transplantation. Clin Transplant, 2008. 22: 719. https://pubmed.ncbi.nlm.nih.gov/18673376 Matheus, W.E., et al. Kidney transplant anastomosis: internal or external iliac artery? Urol J, 2009. 6: 260. https://pubmed.ncbi.nlm.nih.gov/20027554 El-Sherbiny, M., et al. The use of the inferior epigastric artery for accessory lower polar artery revascularization in live donor renal transplantation. Int Urol Nephrol, 2008. 40: 283. https://pubmed.ncbi.nlm.nih.gov/17721826 Firmin, L.C., et al. The use of explanted internal iliac artery grafts in renal transplants with multiple arteries. Transplantation, 2010. 89: 766. https://pubmed.ncbi.nlm.nih.gov/20308866 Oertl, A.J., et al. Saphenous vein interposition as a salvage technique for complex vascular situations during renal transplantation. Transplant Proc, 2007. 39: 140. https://pubmed.ncbi.nlm.nih.gov/17275492 Tozzi, M., et al. Treatment of aortoiliac occlusive or dilatative disease concomitant with kidney transplantation: how and when? Int J Surg, 2013. 11 Suppl 1: S115. https://pubmed.ncbi.nlm.nih.gov/24380542 Franchin, M., et al. ePTFE suture is an effective tool for vascular anastomosis in kidney transplantation. Ital J Vasc Endovasc Surg, 2015. 22: 61. https://www.researchgate.net/publication/285219004_ePTFE_suture_is_an_effective_tool_for_ vascular_anastomosis_in_kidney_transplantation Izquierdo, L., et al. Third and fourth kidney transplant: still a reasonable option. Transplant Proc, 2010. 42: 2498. https://pubmed.ncbi.nlm.nih.gov/20832531 Blanco, M., et al. Third kidney transplantation: a permanent medical-surgical challenge. Transplant Proc, 2009. 41: 2366. https://pubmed.ncbi.nlm.nih.gov/19715921 Nourbala, M.H., et al. Our experience with third renal transplantation: results, surgical techniques and complications. Int J Urol, 2007. 14: 1057. https://pubmed.ncbi.nlm.nih.gov/18036037 Musquera, M., et al. Orthotopic kidney transplantation: an alternative surgical technique in selected patients. Eur Urol, 2010. 58: 927. https://pubmed.ncbi.nlm.nih.gov/20888120 Heylen, L., et al. The Impact of Anastomosis Time During Kidney Transplantation on Graft Loss: A Eurotransplant Cohort Study. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2017. 17: 724. https://pubmed.ncbi.nlm.nih.gov/27593738 Weissenbacher, A., et al. The faster the better: anastomosis time influences patient survival after deceased donor kidney transplantation. Transpl Int, 2015. 28: 535. https://pubmed.ncbi.nlm.nih.gov/25557890 McCulloch, P., et al. IDEAL framework for surgical innovation 1: the idea and development stages. BMJ, 2013. 346: f3012. https://pubmed.ncbi.nlm.nih.gov/23778427 Breda, A., et al. Robot-assisted Kidney Transplantation: The European Experience [Figure presented]. Eur Urol, 2018. 73: 273. https://www.europeanurology.com/article/S0302-2838(17)30721-2/pdf Gallioli, A., et al. Learning Curve in Robot-assisted Kidney Transplantation: Results from the European Robotic Urological Society Working Group. Eur Urol, 2020. https://www.europeanurology.com/article/S0302-2838(19)30947-9/fulltext

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Tzvetanov, I.G., et al. Robotic kidney transplantation in the obese patient: 10-year experience from a single center. Am J Transplant, 2020. 20: 430. https://pubmed.ncbi.nlm.nih.gov/31571369 Basu, A., et al. Adult dual kidney transplantation. Curr Opin Organ Transplant, 2007. 12: 379. https://journals.lww.com/co-transplantation/Abstract/2007/08000/Adult_dual_kidney_ transplantation.10.aspx Haider, H.H., et al. Dual kidney transplantation using midline extraperitoneal approach: description of a technique. Transplant Proc, 2007. 39: 1118. https://pubmed.ncbi.nlm.nih.gov/17524907 Ekser, B., et al. Technical aspects of unilateral dual kidney transplantation from expanded criteria donors: experience of 100 patients. Am J Transplant, 2010. 10: 2000. https://pubmed.ncbi.nlm.nih.gov/20636454 Nghiem, D.D. Simultaneous double adult kidney transplantation using single arterial and venous anastomoses. Urology, 2006. 67: 1076. https://pubmed.ncbi.nlm.nih.gov/16581114 Veroux, P., et al. Two-as-one monolateral dual kidney transplantation. Urology, 2011. 77: 227. https://pubmed.ncbi.nlm.nih.gov/20399490 Salehipour, M., et al. En-bloc Transplantation: an Eligible Technique for Unilateral Dual Kidney Transplantation. Int J Organ Transplant Med, 2012. 3: 111. https://pubmed.ncbi.nlm.nih.gov/25013633 Rigotti, P., et al. A single-center experience with 200 dual kidney transplantations. Clin Transplant, 2014. 28: 1433. https://pubmed.ncbi.nlm.nih.gov/25297945 Al-Shraideh, Y., et al. Single vs dual (en bloc) kidney transplants from donors 4 cm). However, recurrent urinary tract infections (UTIs) may be the only symptom [19, 20]. In children, symptoms may also include pulling of the penis, difficulties in micturition, urinary retention, enuresis and rectal prolapse (resulting from straining due to bladder spasms). Bladder stones may also be an incidental finding in 10% of cases [17, 36].

3.3

Diagnostic evaluation

3.3.1 Diagnostic investigations for bladder stones Plain X-ray of kidney ureter bladder (KUB) has a reported sensitivity of 21%-78% for cystoscopically detected bladder stones in adults [19, 37]. Larger (> 2.0 cm) stones are more likely to be radiopaque [37]. However, plain X-Ray provides information on radio-opacity which may guide treatment and follow-up [23]. Ultrasound (US) has a reported sensitivity and specificity of 20-83% and 98-100%, respectively for the detection of bladder stones in adults [38, 39]. Computer tomography (CT) and cystoscopy have a higher sensitivity for detecting bladder stones than US or X-Ray in adults [38, 39]. No study compares cystoscopy and CT for the diagnosis of bladder stones. Cystoscopy has the advantage of detecting other potential causes for a patient’s symptoms (e.g., bladder cancer), whilst CT can also assess upper tract urolithiasis [23, 40]. There is a paucity of evidence for the investigation of bladder stones, particularly in children [41, 42]. See also EAU Guidelines on Urolithiasis, Section 3.3, for further information on diagnostic imaging for urolithiasis [23]. The principle of ALARA (As Low As Reasonably Achievable) should be applied, especially in children [43].

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3.3.2 Diagnosing the cause of bladder stones The cause of the bladder stone should be considered prior to bladder stone treatment as eliminating the underlying cause will reduce recurrence rates [44]. The following should be performed where possible prior to (or at the time of) bladder stone treatment: • physical examination of external genitalia, peripheral nervous system (including digital rectal examination, peri-anal tone and sensation in men); • uroflowmetry and post-void residual urine assessment; • urine dipstick to include pH ± culture; • metabolic assessment (see also EAU Guideline on Urolithiasis section 3.3.2.3) including: serum (creatinine, (ionised) calcium, uric acid, sodium, potassium, blood cell count); • urine pH; • stone analysis: in first-time formers using a valid procedure (X-ray diffraction or infrared spectroscopy). The following investigations should also be considered for selected patients: • upper tract imaging (in patients with a history of urolithiasis or loin pain); • cysto-urethroscopy or urethrogram.

3.4

Disease Management

3.4.1 Conservative treatment and Indications for active stone removal Migratory bladder stones in adults may typically be left untreated, especially asymptomatic small stones. Rates of spontaneous stone passage are unknown, but data on ureteric stones suggest stones < 1 cm are likely to pass in the absence of BOO, bladder dysfunction or long-term catheterisation [23]. Primary and secondary bladder stones are usually symptomatic and are unlikely to pass spontaneously: active treatment of such stones is usually indicated. 3.4.2 Medical management of bladder stones There is a paucity of evidence on chemolitholysis of bladder stones. However, guidance on the medical management of urinary tract stones in Chapter 3.4.9 of the EAU Urolithiasis Guidelines [23] can be applied to urinary stones in all locations. Uric acid stones can be dissolved by oral urinary alkalinisation when a PH > 6.5 is consistently achieved, typically using an alkaline citrate or sodium bicarbonate. Regular monitoring is required during therapy [23]. Irrigation chemolysis is also possible using a catheter; however, this is time consuming and may cause chemical cystitis and is therefore not commonly employed [45, 46]. 3.4.3 Bladder stone interventions Minimally invasive techniques for the removal of bladder stones have been widely adopted to reduce the risk of complications and shorten hospital stay and convalescence. Bladder stones can be treated with open, laparoscopic, robotic assisted laparoscopic, endoscopic (transurethral or percutaneous) surgery or extracorporeal shock wave lithotripsy (SWL) [4]. 3.4.3.1 Suprapubic cystolithotomy Open suprapubic cystolithotomy is very effective, but is associated with a need for catheterisation and longer hospital stay in both adults and children compared to all other stone removal modalities [4]. In children, a non-randomised study found that, if the bladder was closed meticulously in two layers, “tubeless” (drain-less and catheter-less) cystolithotomy was associated with a significantly shorter length of hospital stay compared with traditional cystolithotomy, without significant differences regarding late or intra-operative complications provided that children with prior UTI, recurrent stones, or with previous surgery for anorectal malformation (or other relevant surgery) were excluded [47]. 3.4.3.2 Transurethral cystolithotripsy In both adults and children, transurethral cystolithotripsy provides high stone-free rates (SFR) and appears to be safe, with a very low-risk of unplanned procedures and major post-operative and late complications [4]. 3.4.3.2.1 Transurethral cystolithotripsy in adults In adults, meta-analysis of four RCTs including 409 patients demonstrated that transurethral cystolithotripsy has a shorter hospital stay and convalescence with less pain, but equivalent SFR and complications compared to percutaneous cystolithotripsy [4]. Transurethral cystolithotripsy with a nephroscope was quicker than percutaneous cystolithotripsy in three RCTs, although transurethral cystolithotripsy with a cystoscope was slower than percutaneous cystolithotripsy [4].

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Rates of urethral strictures following transurethral procedures were not robustly reported: studies report rates between 2.9% and 19.6% during a follow up of 12 – 24 months [4, 30, 48]. One small RCT demonstrated a shorter duration of catheterisation, hospital stay and procedure with transurethral cystolithotripsy than open cystolithotomy with similar SFR [4]. Meta-analysis of four RCTs found shorter procedure duration for transurethral cystolithotripsy using a nephroscope vs. cystoscope with similar SFRs, hospital stay, convalescence, pain, and complications [4, 30, 49-51]. Two retrospective studies (n=188) reported that using a resectoscope or nephroscope was associated with a shorter procedure duration (p < 0.05) than a cystoscope for transurethral cystolithotripsy [52, 53]. This suggests that transurethral cystolithotripsy is quicker when using a continuous flow instrument. 3.4.3.2.1.1 Lithotripsy modalities used during transurethral cystolithotripsy in adults When considering lithotripsy modalities for transurethral cystolithotripsy, the Panel’s systematic review found very low-quality evidence from five non-randomised studies (n=385) which found no difference in SFR between modalities (mechanical, laser, pneumatic, ultrasonic, electrohydraulic lithotripsy [EHL] or washout alone) [4]. Unplanned procedures and major post-operative complications were low-rate events and were not significantly different between lithotripsy modalities, although one non-randomised study (NRS) suggested these might be higher with EHL or mechanical lithotripsy than pneumatic or ultrasonic lithotripsy [54]. All outcomes had very low-quality of evidence (GRADE) [4]. While the laser power setting (30W vs. 100W) does not seem to influence lithotripsy time significantly [31], laser lithotripsy was faster than pneumatic lithotripsy (MD 16.6 minutes; CI: 23.51-9.69, p < 0.0001) in one NRS (n=62); however, a laser was used with a resectoscope and the pneumatic device with a cystoscope [55]. Continuous vs. intermittent irrigating instrument may affect the operation time more significantly than the choice of lithotripsy device [4]. 3.4.3.2.1.2 Transurethral cystolithotripsy in children In children, three NRS suggest that transurethral cystolithotripsy has a shorter hospital stay and catheterisation time than open cystolithotomy, but similar stone-free and complication rates [4, 56]. One small quasi RCT found a shorter procedure time using laser vs. pneumatic lithotripsy for < 1.5 cm bladder stones with no difference in SFR or other outcomes [4, 57]. 3.4.3.3 Percutaneous cystolithotripsy 3.4.3.3.1 Percutaneous cystolithotripsy in adults: One NRS found a shorter duration of procedure and catheterisation and less blood loss for percutaneous, compared with open surgery in adult male patients with urethral strictures; all patients in both groups were rendered stone-free [32]. Meta-analysis of four RCTs comparing transurethral and percutaneous cystolithotripsy found a shorter hospital stay for transurethral cystolithotripsy over percutaneous surgery. Transurethral cystolithotripsy was quicker when using a nephroscope. There were no significant differences in SFRs, major post-operative complications or re-treatment [4]. 3.4.3.3.2 Percutaneous cystolithotripsy in children: In children, three NRS suggest that percutaneous cystolithotripsy has a shorter hospital stay and catheterisation time, but a longer procedure duration and more peri-operative complications than open cystolithotripsy; SFRs were similar [4, 36, 56]. Two small NRS compared percutaneous and transurethral cystolithotripsy and both found similar SFRs, but that transurethral surgery offers a shorter duration of catheterisation and hospital stay [36, 56]. One small NRS found a non-significant increased risk of unplanned procedures (within 30 days of primary procedure) and major post-operative complications for percutaneous operations compared with transurethral procedures; however, age and stone size determined which intervention children underwent and all patients were rendered stone-free [36]. Urethral stricture rates were not robustly compared in either study. 3.4.3.4 Extracorporeal shock wave lithotripsy Extracorporeal SWL is the least invasive therapeutic procedure [4]. 3.4.3.4.1 Shock wave lithotripsy in adults In adults, one RCT compared SWL with transurethral cystolithotripsy in 100 patients with ≤ 2 cm bladder stones presenting with acute urinary retention. Stone free rate after one SWL session favored transurethral

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cystolithotripsy (86% vs. 98%, p=0.03); however, following up to three sessions of SWL, there was no significant difference in SFR (94% vs. 98%, p=0.3) [4, 58]. Two NRS compared transurethral cystolithotripsy vs. SWL and found no significant difference in SFR (97.0% vs. 93.9%, p=0.99, 97.7% vs. 89.7% p=0.07) despite larger stones in transurethral cystolithotripsy patients (4.2 vs. 2.5 cm, p=0.014; and 3.6 vs. 2.6 cm [p value not reported]) [59, 60]. Length of hospital stay appeared to favour SWL in all three studies (0 vs. 1 day, 4.8 vs. 0 days, p=0.02, 0.8 vs. 2.4 days, respectively) [58-60]. No significant differences in major post-operative or intra-operative complications were reported in any study [58-60]. One NRS compared SWL vs. open cystolithotomy in just 43 patients. Stone sizes were not comparable (2.5 vs. 7.4 cm, p < 0.001). SFR were not significantly different (93.9% vs. 100%, p=0.50). Length of stay favoured SWL. There was no significant difference in intra-operative or major post-operative complications [59]. 3.4.3.4.2 Shock wave lithotripsy in children One large NRS found lower SFR for SWL than both transurethral cystolithotripsy and open cystolithotomy, despite treating smaller stones with SWL. However, the length of hospital stay favoured SWL over open cystolithotomy, although this appeared to be comparable between SWL and transurethral cystolithotripsy [61]. 3.4.3.5 Laparoscopic cystolithotomy Laparoscopic cystolithotomy has been described in adults and is typically performed in combination with simple prostatectomy using either traditional laparoscopy or with robotic assistance [62, 63]. A SR found no studies comparing laparoscopic surgery with other procedures [4]. 3.4.4 Treatment for bladder stones secondary to bladder outlet obstruction in adult men Bladder stones in men aged over 40 years may be caused by BPO, the management of which should also be considered. Bladder stones were traditionally an indication for a surgical intervention for BPO: a doctrine which has been questioned by recent studies. One prospective study reports urodynamics (cystometrogram) findings in 46 men aged > 60 years before and after bladder stone treatment [20]. Only 51% of men had BOO while 10% had detrusor under-activity. Eighteen percent of men had a completely normal urodynamic study and 68% had detrusor over-activity. There was no significant difference between pre- and post-bladder stone removal urodynamic findings [20]. One NRS compared 64 men undergoing transurethral cystolithotripsy with either transurethral resection of prostate (TURP) or medical management for BPO (α-blocker with or without 5-alpha reductase inhibitor). After 28 months follow-up, no men on medication had had a recurrence, but 34% underwent TURP: a high postvoid residual urine volume predicted the need for subsequent TURP [64]. Another observational study of 23 men undergoing cystolithotripsy and commencing medical management for BPO found 22% developed a BPO related complication, including 17% who had recurrent stones [44]. Large studies support the safety of performing BPO and bladder stone procedures during the same operation with no difference in major complications compared to a BPO procedure alone [65-67]. An observational study on 2,271 patients undergoing TURP found no difference in complications except UTIs, which occurred slightly more frequently in patients with simultaneously treated bladder stones: 0% vs. 0.6%, p=0.044 [65]. An observational study of 321 men undergoing Holmium laser enucleation of the prostate (HoLEP) found a higher rate of early post-operative incontinence (26.8% vs. 12.5%, p=0.03) in men having concomitant transurethral cystolithotripsy, but no difference in long-term continence rates [66]. 3.4.5 Special situations 3.4.5.1 Neurogenic bladder and stone formation Patients with a neurogenic bladder secondary to spinal cord injury or myelomeningocele are at increased risk of forming bladder stones. Within eight to ten years, 15-36% of patients with spinal cord injury will develop a bladder stone [26-28]. The absolute annual risk of stone formation in spinal cord injury patients with an indwelling catheter is 4% compared with 0.2% for those voiding with clean intermittent self-catheterisation (CISC) [68]. A study of 2,825 spinal cord injury patients over eight years found a 3.3% incidence of bladder stones: 2% with CISC, 6.6% with indwelling urethral catheter, 11% with a suprapubic catheter and 1.1% in patients voiding using reflex micturition [69]. However, another study of 457 spinal cord injury patients for six months found no

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difference in bladder stones between urethral and suprapubic catheterisation [68]. Spinal cord injury patients with an indwelling urethral catheter are six times more likely to develop bladder stones than patients with normal micturition [28, 69]. The risk of stone recurrence after complete removal in spinal cord injury patients is 16% per year [68]. A RCT of 78 spinal cord injury patients who perform CISC found a significant reduction in bladder stone formation when twice weekly manual bladder irrigations were performed for six months (49% vs. 0%, p=< 0.0001), as well as less symptomatic UTIs (41% vs. 8%; p=0.001) [70]. However, this study excluded patients who developed autonomic dysreflexia during bladder irrigations. The irrigation volume used was not reported. 3.4.5.2 Bladder Augmentation The incidence of vesical calculus formation after bladder augmentation is 2-44% in adults [71-79], and 4-53% in children [80-94]. Following cystoplasty, stones form after 24-31 months in adults [72, 74, 79], and after 25-68 months in children [84, 86, 88, 92, 95-97].The reported cumulative incidence of bladder stone formation after ten years is 28-36% and after twenty years is 41% [93, 98]. Risk factors for bladder stone formation after augmentation include excess mucus production, incomplete bladder emptying, non-compliance with CIC or bladder irrigations, bacteriuria or urinary tract infections (due to urease-producing bacteria), foreign bodies (including staples, mesh, non-absorbable sutures), drainage by vesico-entero-cystostomy (Mitrofanoff or Monti) [72, 75, 77, 78, 83, 84, 86, 98, 99] and voiding by CISC compared with those voiding spontaneously [76]. Gastric segment augmentation confers a lower risk of bladder stones than ileal or colononic segment cystoplasty [80, 83, 84, 86]. In previous stone formers, the rate of recurrence is 15-44% in adults [72-74, 76, 79], and 19-56% in children [80, 83, 84, 86, 88-90, 93, 97, 99]. The risk of recurrence is greatest during the first two years, at about 12% per patient per year, with the risk decreasing with time [97]. Daily, or three-times-weekly bladder irrigations reduce the incidence of bladder stones following bladder augmentation or continent urinary diversion [75, 99]. A randomised study found that daily bladder irrigation with 240 mL of saline reduced stone recurrences (p< 0.0002, p=0.0152) and symptomatic UTIs (p< 0.0001, p< 0.0001) compared to 60mL or 120mL [75]. The frequency of bladder irrigations required is unclear. 3.4.5.3 Urinary diversion The incidence of stone formation after urinary diversion with an ileal or colon conduit is 0-3% [100, 101]. The incidence of stone formation is 0-34% in orthotopic ileal neobladders (Hautmann, hemi-Kock, Studer, T-pouch or w-neobladder) [76, 100, 102-110], and 4-6% in orthotopic sigmoid neobladders (Reddy) [106, 111]. The risk of pouch stone formation is 4-43% in adults with an ileocaecal continent cutaneous urinary diversion (Indiana, modified Indiana, Kock or Mainz I) [76, 100, 101, 109, 112, 113]. The average interval from construction of the urinary diversion to stone detection is 71-99 months [105, 114]. In children, the incidence of neobladder stone formation is 30% after Mainz II diversion (rectosigmoid reservoir) [81], and 27% after Kock ileal reservoir construction [91]. 3.4.5.4 Treatment of stones in patients with bladder augmentation or urinary diversion Stones may be removed by open or endoscopic surgery in patients with bladder augmentation or diversion [90]. However, often access cannot be obtained through a continent vesico-entero-cystostomy without damaging the continence apparatus; hence a percutaneous or open approach is typically preferred [90]. No studies comparing outcomes following procedures for stones in reconstructed or augmented bladders were found. Two observational studies indicate that percutaneous lithotomy can be safely performed with US or CT guidance in patients with reconstructed or augmented bladders [115, 116] and is proposed to offer similar advantages over open surgery to those for percutaneous native bladder surgery. Stone recurrence after successful removal has been reported to be 10-42% [115, 116], but appears to be unrelated to the modality used for stone removal [79, 83, 84, 86, 89, 97].

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Figure 3.4 Management of Bladder stones

* Lithotripsy modality at surgeon’s discretion (e.g., mechanical, laser, pneumatic, ultrasonic). † Prefer “tubeless” procedure (without placing a catheter or drain) for children with primary bladder stones and no prior infection, surgery, or bladder dysfunction where open cystolithotomy is indicated. ** Stone analysis should be sent for all first-time stone formers and in patients who develop a recurrence under pharmacological prevention, early recurrence after interventional therapy with complete stone clearance or late recurrence after a prolonged stone-free period (see main Urolithiasis guideline). †† Use an alkaline citrate or sodium bicarbonate with frequent urine pH monitoring and dose titration to achieve a consistent pH > 6.5. BOO = Bladder Outlet Obstruction, TUCL = Trans-urethral cystolithotripsy, PCCL = Percutaneous Cystolithotripsy, SWL = Shock-wave Lithotripsy.

4.

FOLLOW-UP

There are no studies examining the merits of differing follow-up modalities or frequencies following conservative, medical, or operative treatment of bladder stones in adults or children. Identification and prevention of the cause of bladder stone formation will be crucial to prevent recurrence (see section 3.3.2). In adults, there is a paucity of evidence on dietary modification or medical treatment for the prevention of bladder stone recurrence. Recommendations in the EAU Guideline on Urolithiasis, based on evidence from upper tract stones, constitutes the best available recommendations, especially for migratory bladder stones (see chapter 4 in the main EAU Urolithiasis guideline) [23].

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Where it is possible to address the cause of secondary bladder stones (e.g., treatment of BPO), it is unclear whether metabolic intervention would offer any significant additional benefit in preventing stone recurrence. However, especially where the secondary cause cannot be addressed (e.g., indwelling catheter, neuropathic bladder, bladder augmentation or urinary diversion); metabolic interventions are likely to reduce bladder stone recurrence rates. Regular bladder irrigation reduces the chances of bladder stone recurrence in adults and children with bladder augmentation or continent cutaneous urinary diversion and adults with spinal cord injury who perform CISC (see section 3.3.5) [70, 75, 100]. In children with primary (endemic) bladder stones maintenance of hydration, avoidance of diarrhoea and a mixed cereal diet with milk and Vitamins A and B supplements, with the addition of eggs, meat and boiled cows’ milk after one year of age are recommended to prevent recurrence [33]. Finally, there are contradictory reports on a possible association between bladder calculi and future development of bladder cancer [117-119]. The need for follow-up with regular cystoscopy therefore remains controversial. Summary of evidence The incidence of bladder stones peaks at three years in children (endemic/primary stones in developing countries) and 60 years in adults. The aetiology of bladder stones is typically multi-factorial. Bladder stones can be classified as primary (endemic), secondary (associated with lower urinary tract abnormalities e.g., BPO, neuropathic bladder, foreign body, chronic bacteriuria) or migratory (having formed in the upper tract). In adults, BOO is the most common pre-disposing factor for bladder stone formation. Of men undergoing surgery for BPO, 3-4.7% form bladder stones. Metabolic abnormalities are also likely to contribute to bladder stone formation in patients with secondary bladder stones. Primary (endemic) bladder stones typically occur in children in areas with poor hydration, recurrent diarrhoea, and a diet deficient in animal protein. The following measures are proposed to reduce their incidence: maintenance of hydration, avoidance of diarrhoea, and a mixed cereal diet with milk and Vitamins A and B supplements; with the addition of eggs, meat, and boiled cows’ milk after one year of age. In adults, US has a sensitivity of 20-83% for diagnosing bladder stones. In adults, XR-KUB has a sensitivity of 21-78%; sensitivity increases with stone size. Computer tomography has a higher sensitivity than US for the detection of bladder stones. Cystoscopy has a higher sensitivity than XR-KUB or US for the detection of bladder stones. Endoscopic bladder stone treatments (trans-urethral or percutaneous) are associated with comparable SFRs, but a shorter length of hospital stay, duration of procedure and duration of catheterisation compared to open cystolithotomy in adults. Stone-free rates are lower in patients treated with SWL than those treated with open or endoscopic procedures in both adults and children. Transurethral cystolithotripsy is associated with a shorter length of hospital stay, less pain and a shorter convalescence period than percutaneous cystolithotripsy in adults. Transurethral cystolithotripsy with a nephroscope is quicker than when using a cystoscope with no difference in SFR in adults. Transurethral cystolithotripsy with a resectoscope is quicker than when using a cystoscope with no difference in SFR in adults. Mechanical, pneumatic and laser appear equivalent lithotripsy modalities for use in endoscopic bladder stone treatments in adults and children. Open cystolithotomy without a retropubic drain or urethral catheter (“tubeless”) is associated with a shorter length of hospital stay than traditional cystolithotomy and can be performed safely in children with primary stones and no prior bladder surgery or infections. Bladder stone removal with concomitant treatment for BOO is associated with no significant difference in major post-operative complications when compared to BOO treatment alone in adults. However, concomitant bladder stone treatment does increase the rates of short-term post-operative incontinence and UTI.

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The incidence of bladder stone formation in spinal cord injury patients is 15-36% after eight to ten years. The absolute annual risk of stone formation in spinal cord injury patients is significantly higher with an indwelling catheter compared to those voiding with CISC or spontaneously. The incidence of bladder stone formation after bladder augmentation or vesico-entero-cystostomy is between 2-53% in adults and children. Urinary diversion including orthotopic ileal neobladders, ileocaecal continent cutaneous urinary diversion and rectosigmoid reservoirs is associated with urinary reservoir stone formation in 0-43%. The risk of bladder stone formation in spinal cord injury, bladder augmentation or continent urinary diversion patients is reduced by performing regular bladder irrigation. Recommendations Use ultrasound (US) as first-line imaging with symptoms suggestive of a bladder stone. Use cystoscopy or computer tomography (CT), or kidney-ureter-bladder X-Ray (KUB) to investigate adults with persistent symptoms suggestive of a bladder stone if US is negative. Use X-Ray KUB for adults with confirmed bladder stones to guide treatment options and follow-up. All patients with bladder stones should be examined and investigated for the cause of bladder stone formation, including: • uroflowmetry and post-void residual; • urine dipstick, pH, ± culture; • metabolic assessment and stone analysis (see sections 3.3.2.3 and 4.1 of the Urolithiasis guideline for further details). In selected patients, consider: • upper tract imaging (in patients with a history of urolithiasis or loin pain); • cysto-urethroscopy or urethrogram. Offer oral chemolitholysis for radiolucent or known uric acid bladder stones in adults. Offer adults with bladder stones transurethral cystolithotripsy where possible. Perform transurethral cystolithotripsy with a continuous flow instrument in adults (e.g., nephroscope or resectoscope) where possible. Offer adults percutaneous cystolithotripsy where transurethral cystolithotripsy is not possible or advisable. Suggest open cystolithotomy as an option for very large bladder stones in adults and children. Offer children with bladder stones transurethral cystolithotripsy where possible. Offer children percutaneous cystolithotripsy where transurethral cystolithotripsy is not possible or is associated with a high risk of urethral stricture (e.g., young children, previous urethral reconstruction, and spinal cord injury). Open, laparoscopic, and extracorporeal shock wave lithotripsy are alternative treatments where endoscopic treatment is not advisable in adults and children. Prefer “tubeless” procedure (without placing a catheter or drain) for children with primary bladder stones and no prior infection, surgery, or bladder dysfunction where open cystolithotomy is indicated. Perform procedures for the stone and underlying bladder outlet obstruction (BOO) simultaneously in adults with bladder stones secondary to BOO, where possible. Individualise imaging follow up for each patient as there is a paucity of evidence. Factors affecting follow up will include: • whether the underlying functional predisposition to stone formation can be treated (e.g., TURP); • metabolic risk. Recommend regular irrigation therapy with saline solution to adults and children with bladder augmentation, continent cutaneous urinary reservoir or neuropathic bladder dysfunction, and no history of autonomic dysreflexia, to reduce the risk of stone recurrence.

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Turk, T.M., et al. Incidence of urolithiasis in cystectomy patients after intestinal conduit or continent urinary diversion. World J Urol, 1999. 17: 305. https://pubmed.ncbi.nlm.nih.gov/10552149 Arai, Y., et al. Orthotopic ileal neobladder in male patients: Functional outcomes of 66 cases. Int J Urol, 1999. 6: 388. https://pubmed.ncbi.nlm.nih.gov/10466450 Badawy, A.A., et al. Orthotopic diversion after cystectomy in women: A single-centre experience with a 10-year follow-up. Arab J Urol, 2011. 9: 267. https://pubmed.ncbi.nlm.nih.gov/26579310 Ji, H., et al. Identification and management of emptying failure in male patients with orthotopic neobladders after radical cystectomy for bladder cancer. Urology, 2010. 76: 644. https://pubmed.ncbi.nlm.nih.gov/20573379 Madbouly, K. Large orthotopic reservoir stone burden: Role of open surgery. Urol Ann, 2010. 2: 96. https://pubmed.ncbi.nlm.nih.gov/20981195 Miyake, H., et al. Experience with various types of orthotopic neobladder in Japanese men: Longterm follow-up. Urol Int, 2010. 84: 34. https://pubmed.ncbi.nlm.nih.gov/20173366 Moeen, A.M., et al. Management of neobladder complications: endoscopy comes first. Scan J Urol, 2017. 51: 146. https://pubmed.ncbi.nlm.nih.gov/28635567 Simon, J., et al. Neobladder emptying failure in males: incidence, etiology and therapeutic options. J Urol, 2006. 176: 1468. https://pubmed.ncbi.nlm.nih.gov/16952662 Stein, J.P., et al. The orthotopic T pouch ileal neobladder: Experience with 209 patients. J Urol, 2004. 172: 584. https://pubmed.ncbi.nlm.nih.gov/15247737 Stein, J.P., et al. Complications of the afferent antireflux valve mechanism in the Kock ileal reservoir. J Urol, 1996. 155: 1579. https://pubmed.ncbi.nlm.nih.gov/8627827 Miyake, H., et al. Orthotopic sigmoid neobladder after radical cystectomy: Assessment of complications, functional outcomes and quality of life in 82 Japanese patients. BJU Int, 2010. 106: 412. https://pubmed.ncbi.nlm.nih.gov/19888974 Holmes, D.G., et al. Long-term complications related to the modified Indiana pouch. Urology, 2002. 60: 603. https://pubmed.ncbi.nlm.nih.gov/12385916 Khalil, F., et al. Long-term follow-up after ileocaecal continent cutaneous urinary diversion (Mainz i pouch): A retrospective study of a monocentric experience. Arab J Urol, 2015. 13: 245. https://pubmed.ncbi.nlm.nih.gov/26609442 Marien, T., et al. Characterization of Urolithiasis in Patients Following Lower Urinary Tract Reconstruction with Intestinal Segments. J Endourol, 2017. 31: 217. https://pubmed.ncbi.nlm.nih.gov/27936931 Davis, W.B., et al. Percutaneous imaging-guided access for the treatment of calculi in continent urinary reservoirs. CardioVasc Intervent Radiol, 2002. 25: 119. https://pubmed.ncbi.nlm.nih.gov/11901429 Paez, E., et al. Percutaneous treatment of calculi in reconstructed bladder. J Endourol, 2007. 21: 334. https://pubmed.ncbi.nlm.nih.gov/17444782 Chung, S.-D., et al. A case-control study on the association between bladder cancer and prior bladder calculus. BMC Cancer, 2013. 13: 117. https://pubmed.ncbi.nlm.nih.gov/23497224 Jhamb, M., et al. Urinary tract diseases and bladder cancer risk: a case-control study. Cancer Causes Control, 2007. 18: 839. https://pubmed.ncbi.nlm.nih.gov/17593531 La Vecchia, C., et al. Genital and urinary tract diseases and bladder cancer. Cancer Res, 1991. 51: 629. https://pubmed.ncbi.nlm.nih.gov/1985779

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6.

CONFLICT OF INTEREST

All members of the Bladder Stones Guidelines Panel have provided disclosure statements of all relationships that they have that might be perceived as a potential source of a conflict of interest. This information is publicly accessible through the European Association of Urology website: http://www.uroweb.org/guidelines/. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

7.

CITATION INFORMATION

The format in which to cite the EAU Guidelines will vary depending on the style guide of the journal in which the citation appears. Accordingly, the number of authors or whether, for instance, to include the publisher, location, or an ISBN number may vary. The compilation of the complete Guidelines should be referenced as: EAU Guidelines. Edn. presented at the EAU Annual Congress Milan 2021. ISBN 978-94-92671-13-4. If a publisher and/or location is required, include: EAU Guidelines Office, Arnhem, the Netherlands. http://uroweb.org/guidelines/compilations-of-all-guidelines/ References to individual guidelines should be structured in the following way: Contributors’ names. Title of resource. Publication type. ISBN. Publisher and publisher location, year.

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BLADDER STONES - LIMITED UPDATE MARCH 2021

EAU Guidelines on

Chronic Pelvic Pain D. Engeler (Chair), A.P. Baranowski, B. Berghmans, J. Borovicka, A.M. Cottrell, P. Dinis-Oliveira, S. Elneil, J. Hughes, E.J. Messelink (Vice-chair), A.C. de C Williams Guidelines Associates: B. Parsons, S. Goonewardene, P. Abreu-Mendes, V. Zumstein

© European Association of Urology 2021

TABLE OF CONTENTS

PAGE

1. INTRODUCTION 1.1 Aim 1.2 Publication history 1.3 Available Publications 1.4 Panel composition 1.5 Terminology

5 5 5 5 5 6

2. METHODOLOGY 2.1 Methods 2.2 Review

14 14 15

3. EPIDEMIOLOGY, AETIOLOGY AND PATHOPHYSIOLOGY 3.1 Chronic visceral pain 3.1.1 Incidence 3.1.2 Prevalence 3.1.3 Influence on Quality of Life 3.1.4 Costs 3.1.5 Risk Factors and underlying causes 3.1.5.1 Risk factors 3.1.5.2 Underlying causes 3.1.5.3 Clinical paradigms in visceral pain 3.2 Pelvic Pain 3.2.1 Incidence 3.2.2 Prevalence 3.2.2.1 Primary prostate pain syndrome 3.2.2.2 Primary bladder pain syndrome 3.2.2.3 Sexual pain syndrome 3.2.2.4 Myofascial pain syndromes 3.2.3 Influence on QoL 3.2.4 Costs 3.2.5 Risk factors and underlying causes 3.2.5.1 Primary Prostate Pain Syndrome 3.2.5.2 Primary Bladder Pain Syndrome 3.2.5.3 Primary Scrotal Pain Syndrome 3.2.5.4 Primary Urethral Pain Syndrome 3.2.5.5 Primary Vaginal and Vulvar Pain Syndromes 3.2.5.6 Chronic Pelvic Pain and Prolapse/Incontinence Mesh 3.2.5.7 Chronic post-surgical pain 3.2.5.8 Associated conditions in pelvic pain syndromes 3.3 Abdominal aspects of pelvic pain 3.3.1 Incidence 3.3.2 Prevalence 3.3.3 Influence on QOL 3.3.4 Costs 3.3.5 Risk factors & underlying causes 3.4 Summary of evidence and recommendations: CPPPS and mechanisms

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4. DIAGNOSTIC EVALUATION 4.1 General Evaluation 4.1.1 History 4.1.1.1 Anxiety, depression, and overall function 4.1.1.2 Urological aspects 4.1.1.3 Gynaecological aspects 4.1.1.4 Gastrointestinal aspects 4.1.1.5 Peripheral nerve aspects 4.1.1.6 Myofascial aspects 4.1.2 Physical Evaluation 4.2 Supplemental evaluation

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4.3 4.4 4.5

4.2.1 Assessing pelvic pain and related symptoms 4.2.2 Focused myofascial evaluation 4.2.3 Neurological 4.2.4 Imaging 4.2.5 Laboratory Tests 4.2.6 Invasive tests Diagnostic algorithm Other painful conditions without a urological cause Summary of evidence and recommendations: diagnostic evaluation 4.5.1 Diagnostic evaluation - general 4.5.2 Diagnostic evaluation of PPS 4.5.3 Diagnostic evaluation of primary bladder pain syndrome 4.5.4 Diagnostic evaluation of scrotal pain syndrome 4.5.5 Diagnostic evaluation of urethral pain syndrome 4.5.6 Diagnostic evaluation of gynaecological aspects chronic pelvic pain 4.5.7 Diagnostic evaluation of anorectal pain syndrome 4.5.8 Diagnostic evaluation of nerves to the pelvis 4.5.9 Diagnostic evaluation of sexological aspects in chronic pelvic pain 4.5.10 Diagnostic evaluation of psychological aspects of chronic pelvic pain 4.5.11 Diagnostic evaluation of pelvic floor function

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5. MANAGEMENT 5.1 Conservative management 5.1.1 Pain education 5.1.2 Physical therapy 5.1.3 Psychological therapy 5.1.4 Dietary treatment 5.2 Pharmacological management 5.2.1 Drugs for chronic primary pelvic pain syndrome 5.2.1.1 Mechanisms of action 5.2.1.2 Comparisons of agents used in pelvic pain syndromes 5.2.2 Analgesics 5.2.2.1 Mechanisms of action 5.2.2.2 Comparisons within and between groups in terms of efficacy and safety 5.3 Further management 5.3.1 Nerve blocks 5.3.2 Neuromodulation 5.3.3 Surgery 5.4 Summary of evidence and recommendations: management 5.4.1 Management of primary prostate pain syndrome 5.4.2 Management of primary bladder pain syndrome 5.4.3 Management of scrotal pain syndrome 5.4.4 Management of primary urethral pain syndrome 5.4.5 Management of gynaecological aspects of chronic pelvic pain 5.4.6 Management of primary anorectal pain syndrome 5.4.7 Management of pudendal neuralgia 5.4.8 Management of sexological aspects in chronic pelvic pain 5.4.9 Management of psychological aspects in chronic pelvic pain 5.4.10 Management of pelvic floor dysfunction 5.4.11 Management of chronic/non-acute urogenital pain by opioids

40 40 40 41 42 43 43 43 43 43 47 48

6. EVALUATION OF TREATMENT RESULTS 6.1 Evaluation of treatment 6.1.1 Treatment has not been effective 6.1.1.1 Alternative treatment 6.1.1.2 Referral to next envelope of care 6.1.1.3 Self-management and shared care 6.1.2 Treatment has been effective

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REFERENCES

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8.

CONFLICT OF INTEREST

85

9.

CITATION INFORMATION

85

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1.

INTRODUCTION

1.1

Aim

This guideline plays an important role in the process of consolidation and improvement of care for patients with pelvic pain and associated lower abdominal pain. From both literature and daily practice it has become clear that lower abdominal and pelvic pain are areas still under development. This guideline has been recognised as a cornerstone for important developments that have taken place in the past ten years. This guideline aims to expand the awareness of caregivers in the field of abdominal and pelvic pain and to assist those who treat patients with abdominal and pelvic pain in their daily practice. The guideline is a useful instrument not only for urologists, but also for gynaecologists, surgeons, physiotherapists, psychologists and pain doctors. It must be emphasised that guidelines present the best evidence available to the experts. However following guideline recommendations will not necessarily result in the best outcome. Guidelines can never replace clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions also taking personal values and preferences/individual circumstances of patients into account. Guidelines are not mandates and do not purport to be a legal standard of care. Structure and scope The panel wishes to take advantage of modern methods of delivering guideline information to clinicians dealing with these patients. In 2016, a stepped information structure was made, in alignment with stepped care protocols, using new digital information sources like websites and apps to aid this process. Furthermore, the guideline was changed according to the template used in all other non-oncology guidelines of the EAU. It was recognised that structuring a guideline on chronic pain is quite different from structuring one on another subject. A multi-disciplinary approach is of utmost importance and demands a broad view. In 2016, the guideline was rewritten to be centred around pain instead of being organ-centred. It is partly theoretical to show the importance of using this pain-centred approach. The biggest part, however, deals with the practical approach to diagnostics, treatment and management of patients with abdominal and pelvic pain.

1.2

Publication history

The EAU Guidelines on Chronic Pelvic Pain were first published in 2003 [1] which formed the basis of a scientific publication in European Urology in 2004 [2]. Also, in the 2003 edition the concept of Chronic Pelvic Pain Syndromes (CPPS) was introduced, which is now referred to as “pain as a disease process”. Partial updates of the Chronic Pelvic Pain Guidelines were published in 2008 and formed the basis for another scientific publication in European Urology in the year 2010 [3, 4]. Two chapters were added at that time: Chapter 5 ‘Gastrointestinal aspects of chronic pelvic pain’ and Chapter 7 ‘Sexological aspects of chronic pelvic pain’. In the 2014 edition minor revisions were made in Chapter 5 ‘Gastrointestinal aspects of chronic pelvic pain’ and Chapter 8 ‘Psychological aspects of chronic pelvic pain’. For the 2015 edition the panel critically reviewed the sub-chapter on chronic primary bladder pain syndrome which is now a comprehensive part of the guideline. The fact that this part was so extensive shows that the roots of talking about abdominal pain and pelvic pain lies in the bladder, where Interstitial Cystitis was one of the first subjects addressed talking about pain in urology. The panel has illustrated this in the publication in European Urology in 2013 [5].

1.3

Available Publications

Alongside the full text version, a quick reference document (Pocket Guidelines) is available in print and as an app for iOS and Android devices. These are abridged versions which may require consultation together with the full text version. This reference document follows the updating cycle of the underlying large texts. All available material can be viewed at the EAU website. The EAU website also includes a selection of EAU Guideline articles as well as translations produced by national urological associations: uroweb.org/guideline/ chronicpelvicpain/.

1.4

Panel composition

The panel of experts responsible for this document include four urologists, (one of which has a subspecialisation in neuro-urology and one is a sexologist), two consultants in pain medicine, a uro-gynaecologist, a psychologist, a gastroenterologist and a pelvic physiotherapist, health scientist and (clinical) epidemiologist.

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The panel is also grateful to Ms. J. Birch for her expertise, time and diligence in undertaking a review of these guidelines from a patient perspective.

1.5

Terminology

Definitions of chronic pelvic pain terminology Classification Much debate over the classification of chronic pelvic pain has occurred, is ongoing and will continue in the future. Classification involves three aspects of defining a condition: phenotyping, terminology and taxonomy. Phenotyping Phenotyping is describing the condition. For example, chronic bladder pain may be associated with the presence of Hunner’s lesions and glomerulation on cystoscopy, whereas other bladder pain conditions may have a normal appearance on cystoscopy. These are two different phenotypes. The same is true for irritable bowel syndrome (IBS), which may be sub-divided into that associated primarily with diarrhoea or that with constipation. Phenotyping is based upon mechanisms when they are known (e.g., infection, ischaemic, auto-immune, or neuropathic). In the absence of well-defined mechanisms, describing the condition by its symptoms, signs and, where possible, by investigations, has been demonstrated to have clinical and research validity in many situations. When pain is the main symptom and pain as a disease process is considered the cause, the condition is often referred to as a pain syndrome - a well-defined collection of symptoms, signs and investigation results associated with pain mechanisms and pain perception as the primary complaint. The World Health Organization (WHO) International Classification of Diseases 11th Revision (ICD-11) uses the term Chronic Primary Pain to distinguish these conditions from pain associated with another diagnosis that they refer to as Chronic Secondary Pain (see below). Terminology Terminology is the word(s) that are used within classification, both to name the phenotype and within the definition of the phenotype. Examples of names for phenotypes associated with the bladder include interstitial cystitis, painful bladder syndrome or bladder pain syndrome (BPS). The EAU, the International Society for the study of BPS (known as ESSIC), the International Association for the Study of Pain (IASP) and several other groups have preferred the term bladder pain syndrome. In the pain syndromes, the role of the nervous system in generating the sensations is thought to be pivotal, but the term syndrome is also comprehensive and takes into account the emotional, cognitive, behavioural, sexual and functional consequences of the chronic pain. When defining the phenotype, the terminology used in that definition must also be clear and if necessary defined. One of the most important guiding principles is that spurious terminology should be avoided. Terms that end in “itis” in particular should be avoided unless infection and or inflammation is proven and considered to be the cause of the pain [6]. It must be appreciated that end-organ inflammation may be secondary and neurogenic in origin and not a primary cause of the pain. Taxonomy Taxonomy places the phenotypes into a relationship hierarchy. The EAU approach sub-divides chronic pelvic pain into conditions that are pain syndromes with no obvious diagnosis, chronic primary pelvic pain syndromes (CPPPS) (consistent with ICD-11 Chronic Primary Pain) and those that are non-pain syndromes. The latter are conditions that have well-recognised pathology (e.g., infection, neuropathy or inflammation), whereas the former syndromes do not, and pain as a disease process is the mechanism. Other terms for the nonpain syndromes include “classical conditions”, “well-defined conditions” and “confusable diseases” and the ICD-11 Chronic Secondary Pain. Although the EAU approach deals primarily with urological conditions, this approach to classification can be applied to all conditions associated with pain perception within the pelvis; the classification has been developed to include non-urological pain and was accepted by the IASP for publication in January 2012. Classification of Chronic Pelvic Pain Importance of classification It should be obvious to all that a condition cannot be treated unless it is defined. However, the reasons for classifying chronic pelvic pain go far beyond that. Clues to the mechanism As a result of systematic phenotypic and taxonomic classifications, similarities and differences between conditions become clear. Drawing comparisons between the phenotypes of different disorders allows comparison between disorders such as bladder and bowel pain syndromes, thus facilitating research and treatment. 6

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Guidelines for best treatment options As conditions become better defined, more specific treatment approaches can be adopted. In particular, there will be a move away from treatments based upon spurious terms (e.g., antibiotics and non-steroidal antiinflammatory drugs for the “-itis” conditions). Generic treatments aimed at groups of conditions will be more commonplace and based upon research evidence. Research platform Only by clearly defining the phenotype being investigated can research be valued or applied to the clinical situation. Patient needs A diagnosis, or name, for a set of symptoms can provide patients with a sense of being understood, as well as hope for relief. It may therefore help in acceptance of the problem as chronic, resolution of unfounded fears about its implications (if not life-threatening), and engagement in therapeutic endeavours, as well as in self-management. However, it may also lead to accessing information of variable quality associated with the diagnosis or name, and the possibility of generating new concerns about long-term consequences or about appropriateness of treatment. IASP definitions Sub-dividing pain syndromes There is much debate on the sub-divisions of the pain syndromes within the hierarchical taxonomy. The EAU has led the way in this regard and the guiding principles are as follows [2]: 1.

2.

3.

The pain syndromes are defined by a process of exclusion. In particular, there should be no evidence of infection or inflammation. Investigations by end-organ specialists should therefore be aimed at obtaining a differential diagnosis; repeated, unnecessary investigations are detrimental in the management of chronic pain syndromes. A sub-division phenotype should only be used if there is adequate evidence to support its use. For instance, in non-specific, poorly localised pelvic pain without obvious pathology, only the term chronic primary pelvic pain syndrome (CPPPS) should be used. If the pain can be localised to an organ, then a more specific term, such as rectal pain syndrome, may be used, also potentially with the term primary added. If the pain is localised to multiple organs, then the syndrome is a regional pain syndrome and the term CPPPS should once again be considered. As well as defining the patient by a specific end-organ phenotype, there are several other more general descriptors that need to be considered. These are primarily psychological (e.g., cognitive or emotional), sexual, behavioural and functional. Psychological and behavioural factors are well-established factors which relate to quality of life (QoL) issues and prognosis. In North America a research programme, the MAPP program (Multi-disciplinary Approach to the study of Chronic Pelvic Pain research) has been devised to investigate the importance of these factors and looks at all types of pelvic pain irrespective of the end-organ where the pain is perceived. It also looks at systemic disorder associations, such as the co-occurrence of fibromyalgia, facial pain, or auto-immune disorders. In 2004 the panel introduced the concept of managing the polysymptomatic nature of CPPPS, since then others have developed their own schemes, such as Nickel’s UPOINT [7], modified by Magri et al. [8]. In light of these and other publications, the symptom classification table has been updated (Table 1).

The debate in relation to sub-dividing the pain syndromes remains ongoing. As more information is collected suggesting that the central nervous system (CNS) is involved, and indeed may be the main cause of many CPPPS conditions (e.g., bladder, genitalia, colorectal or myofascial), there is a general tendency to move away from end-organ nomenclature. Only time and good research will determine whether this is appropriate. To enable such research, it is essential to have a framework of classification within which to work. Any hierarchical taxonomy must be flexible to allow change. ICD classification: purpose and uses The International Classification of Diseases is the foundation for the identification of health trends and statistics globally, and the international standard for reporting diseases and health conditions. It is the diagnostic classification standard for all clinical and research purposes. It defines the universe of diseases, disorders, injuries and other related health conditions, listed in a comprehensive, hierarchical fashion [9]. The latest version ICD-11 is available for member states to report with from January 2022.

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The ICD-11 classification for the first time included chronic pain (“chronic pain is pain that persists or recurs for longer than 3 months”) and divided the coding into Chronic Primary Pain (“chronic primary pain is multifactorial: biological, psychological and social factors contribute to the pain syndrome”) and a number of Chronic Secondary Pain conditions (related to cancer, post surgical, musculoskeletal, visceral, neuropathic, headache/orofacial, other). The significance of the inclusion of Chronic Pain as a condition within the ICD-11 should not be underestimated. There are, however, unresolved issues regarding this classification, such as when a condition ends and pain persists, does that term Chronic Secondary Pain become Chronic Primary Pain? [10, 11]. Similarly, the contents of recent draft NICE guidelines [12] (https://www.nice.org.uk/guidance/GID-NG10069/ documents/draft-guideline), were found to be contentious as the guidelines considered all Chronic Primary Pain as being essentially the same and the ‘biological’ nature of the pain appeared to have been missed. Whereas in the final guidelines this may be corrected, it does illustrate the risk behind the term Chronic Primary Pain. The panel will change the EAU terminology previously used in the Guidelines to show conformity with ICD 11 definitions. This will include changing terminology used in originally cited works.

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Chronic pelvic pain

Chronic primary pelvic pain syndrome, formally known as pelvic pain syndrome

OR

Chronic secondary pelvic pain syndrome, formally known as specific disease associated pelvic pain

Axis I Region

CHRONIC PELVIC PAIN - LIMITED UPDATE MARCH 2021

Dyspareunia

Pelvic floor muscle Abdominal muscle Spinal

Musculo-skeletal

Coccyx

Any pelvic organ

Psychological

Pelvic pain with sexual dysfunction

Pudendal pain syndrome

Sexological

Intermittent chronic anal

Chronic anal

Irritable bowel

Dysmenorrhoea

CPPPS with cyclical exacerbations

Endometriosis associated

Vulvar Vestibular Clitoral

Post-vasectomy

Penile Urethral

Scrotal Testicular Epididymal

Bladder

Prostate

Axis III End-organ as pain syndrome as identified from Hx, Ex and Ix

Peripheral nerves

Gastrointestinal

Gynaecological

Urological

Axis II System

Suprapubic Inguinal Urethral Penile/clitoral Perineal Rectal Back Buttocks Thighs

Axis IV Referral characteristics

TRIGGER Provoked Spontaneous

TIME Filling Emptying Immediate post Late post

ONGOING Sporadic Cyclical Continuous

ONSET Acute Chronic

Axis V Temporal characteristics Aching Burning Stabbing Electric

Axis VI Character

CUTANEOUS Trophic changes Sensory changes

MUSCLE Function impairment Fasciculation

SEXUOLOGICAL Satisfaction Female dyspareunia Sexual avoidance Erectile dysfunction Medication

NEUROLOGICAL Dysaesthesia Hyperaesthesia Allodynia Hyperalgesia

GASTROINTESTINAL Constipation Diarrhoea Bloatedness Urgency Incontinence

GYNAECOLOGICAL Menstrual Menopause

UROLOGICAL Frequency Nocturia Hesitancy Dysfunctional flow Urgency Incontinence

Axis VII Associated symptoms

PTSD SYMPTOMS Re-experiencing Avoidance

Unattributed

Attributed to other causes

DEPRESSION Attributed to pain or impact of pain

Catastrophic thinking about Pain

ANXIETY About pain or putative cause of pain

Axis VIII Psychological symptoms

The classification has been set up according to the axis system used by IASP.

Table 1: EAU classification of chronic pelvic pain syndromes

Hx = History; Ex = Examination; Ix = Investigation; PTSD = post-traumatic stress disorder.

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Pain syndromes The original EAU classification [2] was inspired by the IASP classification [13] and much work around what has become known as “pain as a disease” and its associated psychological, behavioural, sexual, social and organ function aspects. After ten years of work developing the initial ideas, an updated version was accepted by the IASP Council for publication in January 2012. EAU Definition of chronic pelvic pain Chronic pelvic pain is chronic or persistent pain perceived* in structures related to the pelvis of either men or women. It is often associated with negative cognitive, behavioural, sexual and emotional consequences as well as with symptoms suggestive of lower urinary tract, sexual, bowel, pelvic floor or gynaecological dysfunction. [*Perceived indicates that the patient and clinician, to the best of their ability from the history, examination and investigations (where appropriate) have localised the pain as being discerned in a specified anatomical pelvic area.] In the case of documented nociceptive pain that becomes chronic/persistent through time, pain must have been continuous or recurrent for at least three months (in accordance with ICD-11). For cyclical pain, a longer period of more than six months may be appropriate. Cyclical pain is included in the classification, particularly if there is evidence of central sensitisation and hence dysmenorrhoea (hormonally dependent) needs to be considered as a chronic pain syndrome, if it is persistent and associated with negative cognitive, behavioural, sexual, or emotional consequences. Chronic pelvic pain may be sub-divided into conditions with well-defined classical pathology (such as infection or cancer) and those with no obvious pathology but still including biological mechanisms. For the purpose of the EAU’s classification, the term “specific disease-associated pelvic pain” has been accepted for the former, and “chronic pelvic pain syndrome” for the latter. In the new ICD-11 these conditions have new names: the former will be called Chronic Secondary Pelvic Pain and the latter Chronic Primary Pelvic Pain. The following classification only deals with Chronic Primary Pelvic Pain Syndromes. EAU Definition of chronic primary pelvic pain syndrome Chronic primary pelvic pain syndrome (CPPPS) is the occurrence of chronic pain when there is no proven infection or other obvious local pathology that may account for the pain. It is often associated with negative cognitive, behavioural, sexual or emotional consequences, as well as with symptoms suggestive of lower urinary tract, sexual, bowel or gynaecological dysfunction. Chronic Primary Pelvic Pain Syndrome is a subdivision of chronic pelvic pain. Throughout the text below in the 2021 update, CPPS is replaced with CPPPS if it is appropriate. Further subdivision of CPPPS Pain perception in CPPPS may be focused within a single organ, more than one pelvic organ and even associated with systemic symptoms such as chronic fatigue syndrome (CFS), fibromyalgia (FM) or Sjögren’s syndrome. When the pain is localised to a single organ, some specialists may wish to consider using an end organ term such as Bladder Pain Syndrome (Table 2), also using the term primary. The use of such a phrase with the terminology “syndrome” indicates that, although peripheral mechanisms may exist, CNS neuromodulation may be more important and systemic associations may occur. When the pain is localised to more than one organ site, the generic term CPPPS should be used. Many, including some of the panel members never sub-divide by anatomy and prefer to refer to patients with pain perceived within the pelvis, and no specific disease process, as suffering from CPPPS, sub-divided by psychological and functional symptoms. Psychological considerations for classification Many CPPPSs are associated with a range of concurrent negative psychological, behavioural and sexual consequences that must be described and assessed. Examples that need to be considered are depression, anxiety, fears about pain or its implications, unhelpful coping strategies, and distress in relationships. Both anxiety and depression can be significant important concomitant symptoms that are relevant to pain, disability and poor QoL. Catastrophic interpretation of pain has been shown to be a particularly salient variable, predicting patients’ report of pain, disability, and poor QoL, over and above psychosocial variables such as depression or behavioural factors such as self-reported sexual dysfunction. It is suggested that CPPPS sometimes creates a sense of helplessness that can be reported as overwhelming, and may be associated with the refractory nature of the patients’ symptoms. It is important to note that many of these biopsychosocial consequences are common to other persistent pain problems but may show varying degrees of importance for any one individual suffering from CPPPS. In all patients with CPPPS, these consequences must be

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clearly described as part of the phenotype (where the term phenotype is used to indicate the observable characteristics of the syndrome). Functional considerations for classification Functional disorders, for the purpose of this document, are pathologies that have arisen secondary to changes in the control mechanisms of an organ or system. That is, they are disorders characterised by disturbance of function. As an example, slow colonic transit is a functional disorder of the bowel - the normal function of the bowel is not occurring as a result of changes in the mechanisms that produce defecation, and therefore bowel control is altered. The term is not used in the sense of a psychiatric functional disorder. Many CPPPSs are associated with functional abnormalities at a local and even systemic level. These also need to be defined as a part of the phenotype. Functional pain disorders may not include significant pathology in the organs that appear responsible for the primary symptoms, but they are associated with substantial neurobiological, physiological and sometimes anatomical changes in the CNS. Multi-system sub-division It is recognised that the end-organ where the pain is perceived may not be the centre of pain generation. This classification is based upon the most effective and accepted method of classifying and identifying different pain syndromes, that is, by site of presentation. It is argued that keeping the end-organ name in the classification is inappropriate because, in most cases, there are multi-systemic causes and effects, with the result that symptoms are perceived in several areas. This is an area in which discussions are ongoing, and despite there being strong arguments for both keeping and dispensing with end-organ classification, the panel have not taken the umbrella approach of referring to all pain perceived in the pelvis as CPPS, primary or secondary. Dyspareunia Dyspareunia is defined as pain perceived within the pelvis associated with penetrative sex. It tells us nothing about the mechanism and may be applied to women and men. It is usually applied to penile penetration, but is often associated with pain during insertion of any object. It may apply to anal as well as vaginal intercourse. It is classically sub-divided into superficial and deep. Primary perineal pain syndrome Perineal pain syndrome is a neuropathic-type pain that is perceived in the distribution area of the pudendal nerve, and may be associated with symptoms and signs of rectal, urinary tract or sexual dysfunction. There is no proven obvious pathology. It is often associated with negative cognitive, behavioural, sexual and emotional consequences, as well as with symptoms suggestive of lower urinary tract, sexual, bowel or gynaecological dysfunction. Primary perineal pain syndrome should be distinguished from pudendal neuralgia which is a specific disease associated with perineal pain that is caused by nerve damage. Table 2: C  hronic Primary Pelvic Pain Syndromes (the term primary can be included in any of the following) Urological Pain Syndromes Primary prostate Primary prostate pain syndrome (PPPS) is the occurrence of persistent or recurrent pain syndrome episodic pain (which is convincingly reproduced by prostate palpation). There is no proven infection or other obvious local pathology. Primary prostate pain syndrome is often associated with negative cognitive, behavioural, sexual or emotional consequences, as well as with symptoms suggestive of lower urinary tract and sexual dysfunction. The term “chronic prostatitis” continues to be equated with that of PPPS. In the authors’ and others’ opinion, this is an inappropriate term, although it is recognised that it has a long history of use. The National Institutes of Health (NIH) consensus [14] includes infection (types I and II), which the authors feel should not be considered under PPPS, but as specific disease-associated pelvic pain. The term prostadynia has also been used in the past but is no longer recommended by the expert panel. Please note that some of the authors of the IASP document disagree with this term and suggest that CPPPS of the male is used instead of PPPS, which has been agreed by the majority.

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Primary bladder pain syndrome

Primary bladder pain syndrome (PBPS) is the occurrence of persistent or recurrent pain perceived in the urinary bladder region, accompanied by at least one other symptom, such as pain worsening with bladder filling and day-time and/or night-time urinary frequency. There is no proven infection or other obvious local pathology. Primary bladder pain syndrome is often associated with negative cognitive, behavioural, sexual or emotional consequences, as well as with symptoms suggestive of lower urinary tract and sexual dysfunction. PBPS is believed to represent a heterogeneous spectrum of disorders. There may be specific types of inflammation as a feature in subsets of patients. Localisation of the pain can be difficult by examination, and consequently, another localising symptom is required. Cystoscopy with hydrodistension and biopsy may be indicated to define phenotypes. Recently, ESSIC has suggested a standardised scheme of sub-classifications [15] to acknowledge differences and make it easier to compare various studies. Other terms that have been used include “interstitial cystitis”, “painful bladder syndrome”, and “PBS/IC” or “BPS/IC”. These terms are no longer recommended. Primary scrotal Primary scrotal pain syndrome is the occurrence of persistent or recurrent episodic pain syndrome pain localised to the scrotum or the structure within it and may be associated with symptoms suggestive of lower urinary tract or sexual dysfunction. There is no proven infection or other obvious local pathology. Primary scrotal pain syndrome is often associated with negative cognitive, behavioural, sexual or emotional consequences. Primary scrotal pain syndrome is a generic term and is used when the site of the pain is not clearly testicular or epididymal. The pain is not in the skin of the scrotum as such, but perceived within its contents, in a similar way to idiopathic chest pain. Primary testicular Primary testicular pain syndrome is the occurrence of persistent or recurrent episodic pain syndrome pain perceived in the testes, and may be associated with symptoms suggestive of lower urinary tract or sexual dysfunction. There is no proven infection or other obvious local pathology. Primary testicular pain syndrome is often associated with negative cognitive, behavioural, sexual or emotional consequences. Previous terms have included orchitis, orchialgia and orchiodynia. These terms are no longer recommended. Primary epididymal Primary epididymal pain syndrome is the occurrence of persistent or recurrent episodic pain syndrome pain perceived in the epididymis, and may be associated with symptoms suggestive of lower urinary tract or sexual dysfunction. There is no proven infection or other obvious local pathology. Primary epididymal pain syndrome is often associated with negative cognitive, behavioural, sexual or emotional consequences. Primary penile Primary penile pain syndrome is the occurrence of pain within the penis that is not pain syndrome primarily in the urethra, in the absence of proven infection or other obvious local pathology. Primary penile pain syndrome is often associated with negative cognitive, behavioural, sexual or emotional consequences, as well as with symptoms suggestive of lower urinary tract and sexual dysfunction. Primary urethral Primary urethral pain syndrome is the occurrence of chronic or recurrent episodic pain pain syndrome perceived in the urethra, in the absence of proven infection or other obvious local pathology. Primary urethral pain syndrome is often associated with negative cognitive, behavioural, sexual or emotional consequences, as well as with symptoms suggestive of lower urinary tract, sexual, bowel or gynaecological dysfunction. Primary urethral pain syndrome may occur in men and women. Post-vasectomy Post-vasectomy scrotal pain syndrome is a scrotal pain syndrome that follows scrotal pain vasectomy. Post-vasectomy scrotal pain syndrome is often associated with negative syndrome cognitive, behavioural, sexual or emotional consequences, as well as with symptoms suggestive of lower urinary tract and sexual dysfunction. Post-vasectomy pain may be as frequent as 1% following vasectomy, possibly more frequent. The mechanisms are poorly understood and for that reason it is considered by some a special form of primary scrotal pain syndrome.

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Primary Gynaecological Pain Syndromes: external genitalia Primary vulvar Primary vulvar pain syndrome is the occurrence of persistent or recurrent episodic pain syndrome vulvar pain. There is no proven infection or other local obvious pathology. It is often associated with negative cognitive, behavioural, sexual or emotional consequences, as well as with symptoms suggestive of lower urinary tract, sexual, bowel or gynaecological dysfunction. Although pain perceived in the vulva was included under sexual disorders in the DSM-IV-R manual for classifying psychiatric disorders, there is no scientific basis for this classification, and pain perceived in the vulva is best understood as a pain problem that usually has psychological consequences. There is no evidence for its classification as a psychiatric disorder. The International Society for the Study of Vulvovaginal Disease (ISSVD) has used the term vulvodynia, where the panel use the term primary vulvar pain syndrome. According to the ISSVD, vulvodynia is vulvar pain that is not accounted for by any physical findings. The ISSVD has defined vulvodynia as “vulvar discomfort, most often described as burning pain, occurring in the absence of relevant visible findings or a specific, clinically identifiable, neurologic disorder”. If physical findings are present, the patient is said to have vulvar pain due to a specified cause. The ISSVD has sub-divided vulvodynia based on pain location and temporal characteristics of the pain (e.g., provoked or unprovoked). The following definitions are based on that approach. Primary Primary generalised vulvar pain syndrome refers to a vulvar pain syndrome in which the generalised vulvar pain/burning cannot be consistently and precisely localised by point-pressure mapping pain syndrome via probing with a cotton-tipped applicator or similar instrument. Rather, the pain is diffuse and affects all parts of the vulva. The vulvar vestibule (the part that lies between the labia minora into which the urethral meatus and vaginal introitus open) may be involved but the discomfort is not limited to the vestibule. This pain syndrome is often associated with negative cognitive, behavioural, sexual or emotional consequences. Previous terms have included “dysesthetic vulvodynia” and “essential vulvodynia”, but these are no longer recommended. Primary localised Primary localised vulvar pain syndrome refers to pain that can be consistently and vulvar pain precisely localised by point-pressure mapping to one or more portions of the vulva. syndrome Clinically, the pain usually occurs as a result of provocation (touch, pressure or friction). Primary localised vulvar pain syndrome can be sub-divided into primary vestibular pain syndrome and primary clitoral pain syndrome. Primary vestibular Primary vestibular pain syndrome refers to pain that can be localised by point-pressure pain syndrome mapping to the vestibule or is well perceived in the area of the vestibule. Primary clitoral Primary clitoral pain syndrome refers to pain that can be localised by point-pressure pain syndrome mapping to the clitoris or is well-perceived in the area of the clitoris. Gynaecological system: internal pelvic pain syndromes Endometriosis Endometriosis-associated pain syndrome is chronic or recurrent pelvic pain in patients associated pain with laparoscopically confirmed endometriosis, and the term is used when the syndrome symptoms persist despite adequate endometriosis treatment. It is often associated with negative cognitive, behavioural, sexual or emotional consequences, as well as with symptoms suggestive of lower urinary tract, sexual, bowel or gynaecological dysfunction. Many patients have pain above and beyond the endometriotic lesions; this term is used to cover that group of patients. Endometriosis may be an incidental finding, is not always painful, and the degree of disease seen laparoscopically does not correlate with severity of symptoms. As with other patients, they often have more than one end-organ involved. It has been suggested that this phenotype should be removed from the classification because the endometriosis may be irrelevant. Chronic primary Chronic primary pelvic pain syndrome with cyclical exacerbations covers the nonpelvic pain gynaecological organ pain that frequently shows cyclical exacerbations (e.g., IBS or syndrome BPS) as well as pain similar to that associated with endometriosis/adenomyosis but with cyclical where no pathology is identified. This condition is different from dysmenorrhoea, in exacerbations which pain is only present with menstruation. Primary Primary dysmenorrhoea is pain with menstruation that is not associated with welldysmenorrhoea defined pathology. Dysmenorrhoea needs to be considered as a chronic primary pain syndrome if it is persistent and associated with negative cognitive, behavioural, sexual or emotional consequences.

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Gastrointestinal Pelvic Pain Syndromes Irritable bowel Irritable bowel syndrome is the occurrence of chronic or recurrent episodic pain syndrome perceived in the bowel, in the absence of proven infection or other obvious local pathology. Bowel dysfunction is frequent. Irritable bowel syndrome is often associated with worry and pre-occupation about bowel function, and negative cognitive, behavioural, sexual or emotional consequences, as well as with symptoms suggestive of lower urinary tract or gynaecological dysfunction. The above classification is based upon the Rome III Criteria [16]: three months of continuous or recurring symptoms of abdominal pain or irritation that may be relieved with a bowel movement, may be coupled with a change in frequency, or may be related to a change in stool consistency. Two or more of the following are present at least 25% of the time: change in stool frequency (> three bowel movements per day or < three per week); noticeable difference in stool form (hard, loose, watery or poorly formed stools); passage of mucus in stools; bloating or feeling of abdominal distension; or altered stool passage (e.g., sensation of incomplete evacuation, straining, or urgency). Extra-intestinal symptoms include: nausea, fatigue, full sensation after even a small meal, and vomiting. Chronic primary Chronic primary anal pain syndrome is the occurrence of chronic or recurrent episodic anal pain pain perceived in the anus, in the absence of proven infection or other obvious local syndrome pathology. Chronic primary anal pain syndrome is often associated with negative cognitive, behavioural, sexual or emotional consequences, as well as with symptoms suggestive of lower urinary tract, sexual, bowel or gynaecological dysfunction. Intermittent Intermittent chronic primary anal pain syndrome refers to severe, brief, episodic chronic primary pain that seems to arise in the rectum or anal canal and occurs at irregular intervals. anal pain This is unrelated to the need to or the process of defecation. It may be considered a syndrome sub-group of the chronic primary anal pain syndromes. It was previously known as “proctalgia fugax” but this term is no longer recommended. Musculoskeletal System Primary pelvic Primary pelvic floor muscle pain syndrome is the occurrence of persistent or recurrent floor muscle pain episodic pelvic floor pain. There is no proven well-defined local pathology. It is often syndrome associated with negative cognitive, behavioural, sexual or emotional consequences, as well as with symptoms suggestive of lower urinary tract, sexual, bowel or gynaecological dysfunction. This syndrome may be associated with over-activity of, or trigger points within, the pelvic floor muscles. Trigger points may also be found in several muscles, such as the abdominal, thigh and paraspinal muscles and even those not directly related to the pelvis. Primary coccyx Primary coccyx pain syndrome is the occurrence of chronic or recurrent episodic pain pain syndrome perceived in the region of the coccyx, in the absence of proven infection or other obvious local pathology. Primary coccyx pain syndrome is often associated with negative cognitive, behavioural, sexual or emotional consequences, as well as with symptoms suggestive of lower urinary tract, sexual, bowel or gynaecological dysfunction. The term “coccydynia” was used but is no longer recommended. Chronic Pain Post-Surgery Chronic postThe definition of chronic post-surgical pain is chronic pain that develops or increases surgical pain in intensity after a surgical procedure and persists beyond the healing process, i.e., at syndrome least three months after the surgery. There is a separate category for this in the ICD-11 classification.

2.

METHODOLOGY

2.1

Methods

For each recommendation within the guidelines there is an accompanying strength rating form, the basis of which is a modified GRADE methodology [17, 18]. Each strength rating form addresses a number of key elements namely: 1. the overall quality of the evidence which exists for the recommendation, references used in this text are graded according to a classification system modified from the Oxford Centre for Evidence-Based Medicine Levels of Evidence [19];

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2. 3. 4. 5. 6.

the magnitude of the effect (individual or combined effects); the certainty of the results (precision, consistency, heterogeneity and other statistical or study related factors); the balance between desirable and undesirable outcomes; the impact of patient values and preferences on the intervention; the certainty of those patient values and preferences.

These key elements are the basis which panels use to define the strength rating of each recommendation. The strength of each recommendation is represented by the words ‘strong’ or ‘weak’ [17]. The strength of each recommendation is determined by the balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including certainty of estimates), and nature and variability of patient values and preferences. Additional information can be found in the general Methodology section of this print, and online at the EAU website: http://www.uroweb.org/guideline/. A list of associations endorsing the EAU Guidelines can also be viewed online at the above address. The 2012 full text update was based on a systematic review of literature using the Embase and Medline databases, the Cochrane Central Register of controlled trials and the PsycINFO and Bandolier databases to identify the best evidence from randomised controlled trials (RCTs) (Level of Evidence 1 [LE: 1]) according to the rating schedule adapted from the Oxford Centre for Evidence-based Medicine Levels of Evidence. Where no LE: 1 literature could be identified the search was moved down to the next lower level on the rating scale. Extensive use of free text ensured the sensitivity of the searches, resulting in a substantial body of literature to scan. Searches covered the period January 1995 to July 2011 and were restricted to English language publications. In 2017, a scoping search for the previous five years was performed and the guideline was updated accordingly. For the 2021 print, a new section was included on Post-Surgical Pain Syndrome. In addition, the classifications in the Guideline have been amended to reflect ICD-11 released by WHO. The latest version of ICD-11 will be available for member states to report with as from January 2022.

2.2

Review

This document was subject to peer review prior to publication in 2021.

3.

EPIDEMIOLOGY, AETIOLOGY AND PATHOPHYSIOLOGY

3.1

Chronic visceral pain

Definition of pain Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage (IASP Taxonomy). Introduction to chronic pelvic primary pain syndromes Over the years much of the focus for CPPPS has been on peripheral-end-organ mechanisms, such as inflammatory or infective conditions. However, both animal and clinical research have indicated that many of the mechanisms for the CPPPSs are based within the CNS. Although a peripheral stimulus such as infection may initiate the start of a CPPPS condition, the condition may become self-perpetuating as a result of CNS modulation. As well as pain, these central mechanisms are associated with several other sensory, functional, behavioural and psychological phenomena. It is this collection of phenomena that forms the basis of the pain syndrome diagnosis and each individual phenomenon needs to be addressed in its own right through multispecialty and multi-disciplinary care. Although ongoing peripheral organ pathology can produce persistent and chronic pain, the main focus of these guidelines is on CPPPSs in which no peripheral ongoing pathology (such as infection or neoplastic disease) is detected. The main exception is when pain is due to peripheral nerve damage.

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3.1.1 Incidence No adequate data on incidence were found. 3.1.2 Prevalence Across the world [20] chronic pain is prevalent, seriously affecting the quality of people’s social, family, and working lives, with differences between countries attributable to multiple causes, including study methodology. A more recent study in the UK found a prevalence of chronic pelvic pain of 14.8% in women over 25 years [21]. 3.1.3 Influence on Quality of Life Assessing QoL in pelvic pain patients is challenging due to the complex pathology, the multi-faceted nature of the complaints and the overlap between the different pelvic pain syndromes [22, 23]. Pelvic pain syndromes have an impact in terms of QoL [24, 25], depression, anxiety, impaired emotional functioning, insomnia and fatigue [24, 26]. If these aspects are identified and targeted early in the diagnostic process, the associated pain symptoms may also improve. Addressing comorbidities will help in further improving QoL [27]. Quality of life assessment is therefore important in patients with pelvic pain and should include physical, psychosocial and emotional tools, using standardised and validated instruments [25]. Chronic pain is, in many countries, the leading cause of years lost to disability [20], although these figures are dominated by musculoskeletal pain and headache. Chronic pain is often associated with depression and other psychological problems; with loss or reduction of work and of ability to carry out domestic tasks; and, with substantial use of healthcare, often with disappointing outcomes. 3.1.4 Costs No adequate data on costs were found. 3.1.5 Risk Factors and underlying causes 3.1.5.1 Risk factors Risk factors include many different factors from various areas, including genetic, psychological state, recurrent physical trauma and endocrine factors. The endocrine system is involved in visceral function. Significant life events, and in particular, early life events may alter the development of the hypothalamic-pituitary-adrenal axis and the chemicals released. Increased vulnerability to stress is thought to be partly due to increased corticotrophin-releasing hormone (CRH) gene expression. Up-regulation of CRH has been implicated in several pain states such as rectal hypersensitivity to rectal distension. This model suggests an action of CRH on mast cells. A range of stress-related illnesses have been suggested, e.g., IBS and BPS. There is evidence accumulating to suggest that the sex hormones also modulate both nociception and pain perception. Stress can also produce long-term biological changes which may form the relation between chronic pain syndromes and significant early life and adverse life events [28]. Asking the patient about these events is important as they have an effect on a patient’s psychological wellbeing [29, 30]. Genetics also play a role in assessing the risk of developing chronic pain. An individual who has one chronic pain syndrome is more likely to develop another. Family clusters of pain conditions are also observed and animals can be bred to be more prone to apparent chronic pain state. A range of genetic variations have been described that may explain the pain in certain cases; many of these are to do with subtle changes in transmitters and their receptors. However, the picture is more complicated in that developmental, environmental and social factors also influence the situation. Evidence that PBPS may have a genetic component has been presented in several identical twin studies, but genetics may contribute to less than one third of total variation in susceptibility to PBPS [31, 32]. Studies about integrating the psychological factors of CPPPSs are few but the quality is high. Psychological factors are consistently found to be relevant in the maintenance of persistent pelvic and urogenital pain [33]. Beliefs about pain contribute to the experience of pain [34] and symptom-related anxiety and central pain amplification may be measurably linked, as in IBS [35], and catastrophic thinking about pain and perceived stress predict worsening of urological chronic pain over a year [33, 36]. Central sensitisation has been demonstrated in symptomatic endometriosis [37] and central changes are evident in association with dysmenorrhoea and increasingly recognised as a risk for female pelvic pain [38]. The various mechanisms of CNS facilitation, amplification and failure of inhibition, mean that there is no simple relationship between physical findings, pain experienced and resulting distress and restriction of activities. Division of aetiology into

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organic vs. psychogenic is unscientific. Diagnoses that assign women’s pain to psychological origins due to scepticism about the reality or severity of their pain [39, 40] undermines any therapeutic relationship [41]. Pelvic pain and distress may be related [42] in both men and women [43]; as are painful bladder and distress [36]. In a large population based study of men, CPPPS was associated with prior anxiety disorder [44]. The only systematic review [45] of risk factors for chronic non-cyclical pelvic pain in women included, as well as medical variables: sexual or physical abuse (Odds Ratio (OR): 1.51 to 3.49); psychological problems such as anxiety (OR: 2.28, 95% Confidence Interval (CI): 1.41- 3.70) and depression (OR: 2.69, 95% CI: 1.86-3.88); multiple somatic problems (OR: 4.83, 95% CI: 2.50-9.33 and OR: 8.01, 95% CI: 5.16-12.44). Many studies have reported high rates of childhood sexual abuse in adults with persistent pain, particularly in women with pelvic pain [46]. It is hard to establish a causal role for sexual abuse or trauma history, anxiety or depression in women with CPPPS [47-49], the attribution of current pain to past sexual or physical abuse is associated both with current depression [50] and with current overall physical health [51]. There is some evidence for a specific relationship between rape and CPPPS (and with fibromyalgia and functional gastrointestinal disorders) [52]; and, recent sexual assault may prompt presentation of pelvic pain [46, 53]. Few studies have been found of sexual or physical abuse in childhood and pelvic pain in men, although it has known adverse effects on health [52], but men who reported having experienced sexual, physical or emotional abuse had increased odds (3.3 compared to 1.7) for symptoms suggestive of CPPPS [54]. Both sexes should be screened for sexual abuse when presenting with symptoms suggestive of CPPPS, and clinicians should inquire about pelvic pain in patients who have experienced abuse [54]. 3.1.5.2 Underlying causes The mechanisms that serve as an underlying cause for chronic pelvic pain are: 1. 2. 3.

Ongoing acute pain mechanisms [55] (such as those associated with inflammation or infection), which may involve somatic or visceral tissue. Chronic pain mechanisms, which especially involve the CNS [6]. Emotional, cognitive, behavioural and sexual responses and mechanisms [56-58].

Symptoms and signs of neuropathic pain appear to be common in CPPPS patients and assessment of neuropathic pain should be considered in that group of patients. The presence or absence of endometriosis does not seem to change this [59]. Chronic pain mechanisms may include altered resting state neuromotor connectivity, for instance in men with chronic prostatitis/CPPPS [60]. Table 3 illustrates some of the differences between the somatic and visceral pain mechanisms. These underlie some of the mechanisms that may produce the classical features of visceral pain; in particular, referred pain and hyperalgesia.

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Table 3: Comparison between visceral and somatic pain

Effective painful stimuli

Summation Autonomic involvement Referred pain Referred hyperalgesia

Innervation Primary afferent physiology

Silent afferents

Visceral pain Stretching and distension, producing poorly localised pain. Widespread stimulation produces significantly magnified pain. Autonomic features (e.g., nausea and sweating) frequently present. Pain perceived at a site distant to the cause of the pain is common. Referred cutaneous and muscle hyperalgesia is common, as is involvement of other visceral organs. Low density, unmyelinated C fibres and thinly myelinated A∂ fibres. Intensity coding. As stimulation increases, afferent firing increases with an increase in sensation and ultimately pain. 50-90% of visceral afferents are silent until the time they are switched on.

Central mechanisms

Play an important part in the hyperalgesia, viscero-visceral, viscero-muscular and musculovisceral hyperalgesia.

Abnormalities of function

Central mechanisms associated with visceral pain may be responsible for organ dysfunction. As well as classical pathways, there is evidence for a separate dorsal horn pathway and central representation.

Central pathways and representation

Somatic pain Mechanical, thermal, chemical and electrical stimuli, producing well localised pain. Widespread stimulation produces a modest increase in pain. Autonomic features less frequent. Pain is relatively well localised and well recognised. Hyperalgesia tends to be localised.

Dense innervation with a wide range of nerve fibres. Two fibre coding. Separate fibres for pain and normal sensation.

These fibres are very important in the central sensitisation process. Silent afferents present, but form a lower percentage. Sensations not normally perceived become perceived and nonnoxious sensations become painful. Responsible for the allodynia and hyperalgesia of chronic somatic pain. Somatic pain associated with somatic dysfunction, e.g., muscle spasm. Classical pain pathways.

Ongoing peripheral pain mechanisms in visceral pain In most cases of chronic pelvic pain, ongoing tissue trauma, inflammation or infection is absent [61, 62]. However, conditions that produce recurrent trauma, infection or ongoing inflammation may result in chronic pelvic pain in a small proportion of cases. For example, out of a large cohort with acute bacterial prostatitis, 10.5% ended up with a state of CPPPS [63]. It is for this reason that the early stages of assessment include looking for these pathologies [15]. Once excluded, ongoing investigations for these causes are rarely helpful and indeed may be detrimental. When acute pain mechanisms are activated by a nociceptive event, as well as direct activation of the peripheral nociceptor transducers, sensitisation of those transducers may also occur; therefore, magnifying the afferent signalling. Afferents that are not normally active may also become activated by the change, that is, there may be activation of the so-called silent afferents. Although these are mechanisms of acute pain, the increased afferent signalling is often a trigger for the chronic pain mechanisms that maintain the perception of pain in the absence of ongoing peripheral pathology (see below) [64]. There are a number of mechanisms by which the peripheral transducers may exhibit an increase in sensibility: 1. Modification of the peripheral tissue, which may result in the transducers being more exposed to peripheral stimulation. 2. There may be an increase in the chemicals that stimulate the receptors of the transducers [65]. 3. There are many modifications in the receptors that result in them being more sensitive.

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In general, the effect of 1 and 2 is to lower the threshold and the effect of 3 is to increase responsiveness to external stimuli. Some of the chemicals responsible for the above changes may be released from those cells associated with inflammation, but the peripheral nervous system may also release chemicals in the positive and inhibitory loops [66, 67]. Central sensitisation as a mechanism in visceral pain It is important to appreciate that nociception is the process of transmitting information to centres involved in perception of a stimulus that has the potential to cause tissue damage. Pain is far more complex and involves activation of the nociceptive pathways but also the emotional response. The brain may affect the modulation of pain pathways at the spinal cord level. Neuronal sensitisation is responsible for a decrease in threshold and an increase in response duration and magnitude of dorsal horn neurons. It is associated with an expansion of the receptive field. As a result, sensitisation increases signalling to the CNS and amplifies what we perceive from a peripheral stimulus. For example, for cutaneous stimuli, light touch would not normally produce pain, however, when central sensitisation is present, light touch may be perceived as painful (allodynia). In visceral hyperalgesia (so called because the afferents are primarily small fibres), visceral stimuli that are normally sub-threshold and not usually perceived, may be perceived. For instance, with central sensitisation, stimuli that are normally sub-threshold may result in a sensation of fullness and a need to void or to defecate. Non-noxious stimuli may be interpreted as pain and stimuli that are normally noxious may be magnified (true hyperalgesia) with an increased perception of pain. As a consequence, one can see that many of the symptoms of PBPS and IBS may be explained by central sensitisation. A similar explanation exists for the muscle pain in FM. It is now well accepted that there are both descending pain-inhibitory and descending pain-facilitatory pathways that originate from the brain [68]. Several neurotransmitters and neuromodulators are involved in descending pain-inhibitory pathways. The main ones are the opioids, 5-hydroxytryptamine and noradrenaline. The autonomic nervous system also plays a role in sensitisation. There is good evidence that damaged afferent fibres may develop a sensitivity to sympathetic stimulation, both at the site of injury and more centrally, particularly in the dorsal horns. In visceral pain, the efferent output of the CNS may be influenced by central changes (again, those changes may be throughout the neuraxis), and such modification of the efferent message may produce significant end-organ dysfunction. These functional abnormalities can have a significant effect on QoL and must be managed as appropriate. Psychological mechanisms in visceral pain Psychological processes of emotions, thought and behaviour involve networks rather than distinct centres. Some of these processes are sophisticated and others fundamental in evolutionary terms, and their interaction with pain processing is complex. Various psychological processes affect pain neuromodulation at a higher level. Inhibiting or facilitating both the strength of the nociceptive signal reaching the consciousness and appraisal and interpretation of that signal, will also modulate the response to the nociceptive message and hence the pain experience. Further, descending pathways represent cognitive, emotional and behavioural states at spinal and peripheral levels. Functional magnetic resonance imaging (fMRI) has indicated that the psychological modulation of visceral pain probably involves multiple pathways. For instance, mood and attentional focus probably act through different areas of the brain when involved in reducing pain [69]. This psychological modulation may act to reduce nociception within a rapid time frame but may also result in long-term vulnerability to chronic visceral pain, through long-term potentiation. This involvement of higher centre learning may be at both a conscious and subconscious level, and is clearly significant in the supratentorial neuroprocessing of nociception and pain. Long-term potentiation [70] may occur at any level within the nervous system, so that pathways for specific or combinations of stimuli may become established, resulting in an individual being vulnerable to perceiving sensations that would not normally be experienced as painful. An important review [28] of chronic pelvic pain in women dismantles the notion that women without relevant physical findings differ in psychological characteristics from women with relevant physical findings. It argues for better methodology, and for greater use of idiographic methods. Women with pelvic pain often have other non-pain somatic symptoms and current or lifetime anxiety and depression disorder [21]; they may have a history of physical or sexual abuse in childhood of unclear significance. Studies that describe these non-pain

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somatic symptoms as ‘medically unexplained’ or ‘psychosomatic’ or ‘somatoform’ disorders are unhelpful, misinterpreting absence of physical findings to indicate psychological origins of the complaint. Pain studies describe multiple processes by which pain may spread from one site to another, or in time, including central sensitisation (see previous section), viscero-visceral cross sensitisation in relation to multiple pain sites [71], activation of the hypothalamic-pituitary axis and dysregulation of serotonergic pathways [72] that can render pain levels sensitive to stress. Some pain problems which affect sexual activity are diagnosed as sexual problems (e.g., ‘dyspareunia’) when pain is the central problem and not contingent on sexual activity alone [73]. Better integration of sexology and mainstream psychology for pelvic pain in both men and women is needed, building on a biopsychosocial formulation [74, 75]. The term psychosomatic symptoms can best be understood as multiple somatic symptoms not associated with or indicative of any serious disease process. Medical and surgical history may also be important [76]. There have been a few studies of maintenance of, or recovery from, pelvic pain in relation to psychological factors of importance in pain. Those that described pelvic pain as medically unexplained or psychosomatic, due to the lack of physical findings, have been discarded, because such a distinction is inconsistent with known pain mechanisms. Understanding the psychological components of pain Psychological processes of emotions, thought and behaviour involve distributed networks, whose interactions with pain processing are complex, producing inhibition and facilitation of signal processing, appraisal, and response. Models that integrate psychological factors involved in maintaining persistent pelvic and urogenital pain with current neurobiological understanding of pain are few, but the quality is high (see Section 3.1.5.1). There is no evidence that women with CPPPS without physical findings are primarily presenting a psychological problem [28]. Anxiety and post-traumatic stress symptoms are common in some women with CPPPS [40, 77] and with vulvar pain [78], and may account for substantial variance in health status, treatment use and treatment outcome; for instance, women’s expectations about vulvar pain on penetration predicted pain, sexual function and sexual satisfaction [79]. Negative investigative findings do not necessarily resolve women’s anxieties about the cause of pain [80, 81] and anxiety often focuses on what might be ‘wrong’. Depression may be related to pain in various ways, as described above. Until measures are available that are adequately standardised in patients with pain, assessment of anxiety and distress requires questions about the patient’s beliefs about the cause of pain, the hope that diagnosis will validate pain, the struggle with unpredictability, and the implications of pain for everyday life [82, 83]. Reference to the studies of the IMMPACT group [84] is recommended for guidance on outcome measures suitable for pain trials. Stress can modify the nervous system to produce long-term biological changes. These structural changes may be responsible for significant early life and adverse life events which are associated with chronic pain syndromes [30]. The patient should be asked about adverse life events that may produce these biological responses and affect a patient’s general psychological well-being [30, 85]. 3.1.5.3 Clinical paradigms in visceral pain Referred pain Referred pain is frequently observed and its identification is important for diagnosis and treatment. Referral is usually somatic to somatic, or visceral to somatic. However, there is no reason why pain cannot also be perceived within the area of an organ with the nociceptive signal having arisen from a somatic area. Referred pain may occur as a result of several mechanisms but the main theory is one of convergence-projection. In the convergence-projection theory, afferent fibres from the viscera and the somatic site of referred pain converge onto the same second order projection neurons. The higher centres receiving messages from these projection neurons are unable to separate the two possible sites from the origin of the nociceptive signal [64]. Hyperalgesia refers to an increased sensitivity to normally painful stimuli. In patients that have passed a renal stone, somatic muscle hyperalgesia is frequently present, even a year after expulsion of the stone. Pain to non-painful stimuli (allodynia) may also be present in certain individuals. Somatic tissue hyperaesthesia is associated with urinary and biliary colic, IBS, endometriosis, dysmenorrhoea, and recurrent bladder infections. Primary vulvar pain syndromes are examples of cutaneous allodynia that, in certain cases, may be associated with visceral pain syndromes, such as BPS. Referred pain with hyperalgesia is thought to be due to central sensitisation of the converging viscero-somatic neurons. Central sensitisation also stimulates efferent activity that could explain the trophic changes that are often found in the somatic tissues.

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Musculo-skeletal system and pelvic pain In the urogenital pain syndromes, muscle tenderness and trigger points may be implicated as a source of pain. Central mechanisms are of great importance in the pathogenesis of this muscle hyperalgesia. The muscles involved may be a part of the spinal, abdominal or pelvic complex of muscles. It is not unknown for adjacent muscles of the lower limbs and the thorax to become involved. Pain may be localised to the trigger points but it is more often associated with classical referral patterns. As well as trigger points, inflammation of the ligaments and tendons to the bones (enthesitis) and of the bursa (bursitis) may be found [86]. Certain postures affect the different muscles in different ways, and as a consequence, may exacerbate or reduce the pain. Stress has been implicated as both an initiator of pelvic myalgia and as a maintenance factor. As a result, negative sexual encounters may also have a precipitating effect [28]. Visceral hyperalgesia The increased perception of stimuli in the viscera is known as visceral hyperalgesia, and the underlying mechanisms are thought to be responsible for IBS, PBPS and dysmenorrhoea. The mechanisms involved are often acute afferent input (e.g., due to infection) followed by long-term central sensitisation. Viscero-visceral hyperalgesia is thought to be due to two or more organs with converging sensory projections and central sensitisation. For instance, overlap of bladder and uterine afferents or uterine and colon afferents.

3.2

Pelvic Pain

3.2.1 Incidence No adequate data on incidence were found. 3.2.2 Prevalence 3.2.2.1 Primary prostate pain syndrome There is only limited information on the true prevalence of PPPS in the population. As a result of significant overlap of symptoms with other conditions (e.g., benign prostatic enlargement and PBPS), purely symptom based case definitions may not reflect the true prevalence of PPPS [87, 88]. In the literature, population-based prevalence of prostatitis symptoms ranges from 1 to 14.2% [89, 90]. The risk of prostatitis increases with age (men aged 50-59 years have a 3.1-fold greater risk than those aged 20-39 years). 3.2.2.2 Primary bladder pain syndrome Reports of PBPS prevalence have varied greatly, along with the diagnostic criteria and populations studied. Recent reports range from 0.06 to 30% [91-100]. There is a female predominance of about 10:1 [97] but possibly no difference in race or ethnicity [87, 101, 102]. The relative proportions of Hunner’s lesion and nonlesion disease are unclear. Incidence in studies has ranged from 5 to 50% [103-106]. There is increasing evidence that children under eighteen may also be affected, although prevalence figures are low; therefore, PBPS cannot be excluded on the basis of age [107]. 3.2.2.3 Sexual pain syndrome In the 1980s an association between chronic pelvic pain and sexual dysfunction was postulated. In a review the relationship between Primary Prostate Pain Syndrome and health status, with influence on sexual activity, was addressed [108]. In a Chinese study of men with chronic pelvic pain, 1,768 males completed the questionnaires. The overall prevalence of sexual dysfunction was 49%. Erectile dysfunction (ED) is the most investigated sexual dysfunction in PPPS patients. The reported prevalence of ED ranges from 15.1 to 48%, varying with evaluation tools and populations [109, 110]. Erectile dysfunction was prevalent in 27.4% of Italian men aged 25-50 [111], 15.2% among Turkish men (significantly higher than in the control group) [112] and 43% among Finnish men with PPPS [113]. The prevalence of ED was found to be higher in young men with PPPS than in the general population. According to other studies men with pelvic pain had a higher chance of suffering from ED [114]. Recently, a significant correlation between “chronic prostatitis”, chronic pelvic pain symptoms (measured by NIH-CPSI) and ED (measured by International Index of Erectile Function [IIEF]) was confirmed [115], while other studies using the same questionnaires were not able to confirm such a correlation [75, 116]. Some studies also report ejaculatory dysfunction, mainly premature ejaculation [109, 110, 117, 118]. In community-based studies in the UK [119], New Zealand [120] and Australia [121], a substantially larger proportion of the women with chronic pelvic pain reported dyspareunia (varying between 29 and 42%) than women without chronic pelvic pain (varying between 11 and 14%). Only a few studies have investigated sexual problems within clinical populations [122]. Another study showed that all of the sexual function domains (desire, arousal, lubrication, orgasm, satisfaction, and pain) were significantly lower in women with chronic pelvic pain than in women without chronic pelvic pain [122]. In line with the results of community based studies, patients with chronic pelvic pain reported more sexual problems such as dyspareunia, problems with desire or

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arousal and lubrication than women without chronic pelvic pain [122, 123]. One study of patients enrolled in chronic pain treatment programs in England has reported that 73% had pain-related sexual problems [124]. 3.2.2.4 Myofascial pain syndromes The relationship between muscular dysfunction (especially over-activity) and pelvic pain has been found in several studies [125]. Rectal pain treated with pelvic floor muscle therapy is only relieved when patients learn to relax their pelvic floor muscles [126, 127]. The vast majority (92.2%) of men visiting a tertiary centre for pelvic pain had dysfunction of the pelvic floor muscles. This finding was true regardless of evidence of inflammation (prostatitis or cystitis) [128]. This relationship has been found in chronic prostatitis [129], PBPS [130] and vulvar pain [131]. Dysfunction of the pelvic floor directly affects function of the pelvic viscera and vice versa. Both systems can act as the primary signal to the spinal cord, with a cascade of reactions ascending to the CNS as a result. The muscle itself ends up shortened, leading to restrictions even in a relaxed state. 3.2.3 Influence on QoL Data on the influence on QoL will be included in a future version of the guidelines. 3.2.4 Costs No adequate data on costs were found. 3.2.5 Risk factors and underlying causes The risk factors are unspecific for most of the pain syndromes in the pelvic area. They are described in Section 3.1.5.1. The underlying causes, including the mechanisms for the different clinical pain syndromes are described here. 3.2.5.1 Primary Prostate Pain Syndrome Pain is the main symptom in PPPS. As a common feature of primary chronic pain syndromes, no single aetiological explanation has been found. One explanation is that the condition probably occurs in susceptible men exposed to one or more initiating factors, which may be single, repetitive or continuous. Several of these potential initiating factors have been proposed, including infectious, genetic, anatomical, neuromuscular, endocrine, immune (including autoimmune), or psychological mechanisms. These factors may then lead to a peripheral selfperpetuating immunological, inflammatory state and/or neurogenic injury, creating acute and then chronic pain. One recent study showed that chronic but not acute histological inflammation of the prostate was significantly associated with symptomatic progression [132]. Based on the peripheral and the central nervous system, sensitisation involving neuroplasticity may lead to a centralised neuropathic pain state [133]. This could also explain why tissue damage is not usually found in PPPS. There is growing evidence for a neuropathic origin and association with CNS changes of pain in PPPS, and anxiety appears to be a risk factor for its development [44]. 3.2.5.2 Primary Bladder Pain Syndrome An initial unidentified insult to the bladder, leading to urothelial damage, neurogenic inflammation and pain is thought to be a trigger of PBPS. However, PBPS might be a local manifestation of a systemic disorder. No infection has as yet been implicated. Nevertheless, urinary infections are significantly more frequent during childhood and adolescence, in patients with PBPS in adulthood [134]. Experimental induction of chronic pelvic pain by O-antigen deficient bacterial strains supports the bacterial hypothesis [135]. Pancystitis, with associated perineural inflammatory infiltrates, and mast cell count increase is an essential part of PBPS type 3 C [136], but is rare in non-lesion PBPS [30, 69, 137, 138]. Cystoscopic and biopsy findings in both lesion and non-lesion PBPS are consistent with defects in the urothelial glycosaminoglycan (GAG) layer, which might expose submucosal structures to noxious urine components [139-145] and a consequent cytotoxic effect [146, 147]. Basic and clinical studies indicate that autonomic dysfunction with sympathetic predominance may be implicated in PBPS [148, 149]. An association has been reported between PBPS and non-bladder syndromes such as FM, CFS, IBS, vulvodynia, depression, panic disorders, migraine, sicca syndrome, temporomandibular joint disorder, allergy, asthma and systemic lupus erythematosus [150-154]. Risk of PBPS correlates with a number of non-bladder syndromes in each patient [155]. Recent work showing non-lesion PBPS to have significantly more FM, migraine, temporomandibular joint disorder and depression than PBPS type 3 C patients, which emphasises the need for subtyping [156]. 3.2.5.3 Primary Scrotal Pain Syndrome Often scrotal pain is not associated with any specific pathology. Pain is perceived in the testes, epididymis, or the vas deferens. The ilioinguinal, genitofemoral and the pudendal nerves innervate the scrotum [157]. Any pathology or intervention at the origin or along the course of these nerves may result in pain perceived in the scrotum [158].

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Two special forms of scrotal pain syndrome can be described. The first is post-vasectomy scrotal pain syndrome which occurs following vasectomy. The mechanisms are poorly understood, and for that reason it is considered by some a special form of primary scrotal pain syndrome. Incidence of post-vasectomy pain is 2-20% among all men who have undergone a vasectomy [159]. In men with post-vasectomy pain, 2-6% have a Visual Analogue Scale (VAS) score > 5 [160]. In a large cohort study of 625 men, the likelihood of scrotal pain after six months was 14.7%. The mean pain severity on a VAS score was 3.4/10. In the pain group, 0.9% had quite severe pain, noticeably affecting their daily life. In this cohort, different techniques were used to perform the vasectomy. The risk of post-vasectomy pain was significantly lower in the no-scalpel vasectomy group (11.7% vs. the scalpel group 18.8%) [161]. The second special form of scrotal pain is post-inguinal hernia repair pain. It is seen as a complication of hernia repair, but in trials it is seldom reported, or it is put under the term chronic pain (not specified). In studies that have explicitly mentioned scrotal pain, there was a difference in incidence between laparoscopic and open hernia repair. In almost all studies, the frequency of scrotal pain was significantly higher in the laparoscopic than in the open group [158, 162]. In one particular study, there was no difference at one year but after five years, the open group had far fewer patients with scrotal pain [163]. Inguinal hernia repair can lead to chronic post-surgical pain (CPSP) in up to 10% of patients at 6 months [164] and may present with groin and/or scrotal pain. Testicular injury is uncommon (< 1%) but if associated with pain, orchidectomy can lead to symptomatic relief in 2/3 of patients [165]. Careful identification and preservation of nerves has been found to be associated with a reduced risk of chronic pain. 3.2.5.4 Primary Urethral Pain Syndrome Several mechanisms for the development of primary urethral pain syndrome have been proposed. The intimate relationship of the urethra with the bladder (both covered with urothelium) suggests that primary urethral pain syndrome may be a form of PBPS. Mechanisms thought to be basic for PBPS may also apply to the urethra. This means that the specific testing with potassium has been used to support the theory of epithelial leakage [166, 167]. Another possible mechanism is neuropathic hypersensitivity following urinary tract infection [168]. The relationship with gynaecological and obstetric aspects is unclear. In a small group of patients with urethral pain, it has been found that grand multi-parity and delivery without episiotomy were more often seen in patients with urethral syndrome, using univariate analysis [169]. 3.2.5.5 Primary Vaginal and Vulvar Pain Syndromes Pain in the vagina or the female external genital organs is often due to infection or trauma, as a consequence of childbirth or surgery. Pain is usually a precedent to dyspareunia. When the pain persists for more than three months, it can be diagnosed as primary vulvar pain syndrome previously known as “vulvodynia” or “chronic vaginal pain” with no known cause. It is still a poorly understood condition, and therefore difficult to treat. There are two main sub-types of primary vulvar pain syndrome: generalised, where the pain occurs in different areas of the vulva at different times; and focal, where the pain is at the entrance of the vagina. In primary generalised vulvar pain syndrome, the pain may be constant or occur occasionally, but touch or pressure does not initiate it, although it may make the pain worse. In primary focal vulvar pain syndrome, the pain is described as a burning sensation that comes on only after touch or pressure, such as during intercourse. The possible causes of primary vulvar pain syndrome are many and include: • history of sexual abuse; • history of chronic antibiotic use; • hypersensitivity to yeast infections, allergies to chemicals or other substances; • abnormal inflammatory response (genetic and non-genetic) to infection and trauma; • nerve or muscle injury or irritation; • hormonal changes. 3.2.5.6 Chronic Pelvic Pain and Prolapse/Incontinence Mesh Continence and prolapse mesh implants were developed as simple flexible polypropylene plastic acting as a scaffold to treat urinary stress incontinence (USI) and uterovaginal prolapse, respectively. They were deemed easy to insert, but no credence was given as to how safe they were, whether they could be removed should they cause complications, or what to do should they not be effective [170, 171]. Most meshes took less than an hour to implant surgically and most patients were treated as day cases, allowing women to leave hospital quickly and get on with their lives. Therefore, rather than undergo complex traditional surgery, women were offered permanent mesh implants, particularly in the treatment of USI where they were considered to be the gold standard [172, 173]. However, over the last few years the insertion of mesh has come with significant ‘health and safety warnings’ [174, 175]. CHRONIC PELVIC PAIN - LIMITED UPDATE MARCH 2021

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For many, mesh was initially seen not just as an effective treatment but as a permanent one. Complications were thought not be a significant issue and the figure of 1-3% was often quoted. However, we now know the complication rate was closer to 10% [176]. They included chronic pain [177, 178], as well as chronic infections [179], erosion into the surrounding organs including the vagina, urethra and bladder, as well as nerve and musculoskeletal damage affecting mobility [177, 178, 180, 181]. All had a significant impact on the patients’ QoL. It is as a result of severely debilitating complications following mesh implantation [177], that the field of mesh removal medicine and surgery has emerged [182]. Early recognition of possible mesh complications is very important. It is normal to wake up in some degree of discomfort after any surgery. However, if the pain after the operation is very severe and much more than expected after this type of surgery, it can be a sign that there was added trauma to the surrounding organs during the procedure. Most pain is often managed with analgesia, but some women might not fully respond to therapy. If the pain is difficult to treat and does not improve over time, it may become necessary to remove the mesh. Leaving a painful mesh in the pelvis, can lead to chronic pelvic pain. The precise mechanism is unknown but it is thought to be a ‘neuro-inflammatory’ process [183], as has been proposed in hernia mesh neuralgia. The impact of the mesh, regardless of site, appears to be similar. 3.2.5.7 Chronic post-surgical pain Chronic pain may develop following surgical procedures and has a significant impact on the individual. The ICD-11 has recently classified chronic post-surgical pain (CPSP) as a chronic pain condition. The definition of CPSP is chronic pain that develops or increases in intensity after a surgical procedure and persists beyond the healing process, i.e., at least 3 months after the surgery [184]. Chronic post-surgical pain (as start of sentence) may occur in a significant number of patients, and is more prevalent following some operations rather than others. Procedures with a higher risk of CPSP include limb amputation (30-85%), thoracotomy (5-65%) and mastectomy (11-57%) [185]. Risk factors for CPSP include a number of pre-, peri- and post-operative factors. Younger age, female gender, chronic pain pre-operatively elsewhere, higher number of previous operations, use of opioids and a higher post-operative pain score have been found to be associated with a higher risk of CPSP in a prospective cohort of patients undergoing laparoscopy and laparotomies. Older age, malignant indication for surgery, a higher pre-operative mental health score and the use of epidural analgesia in addition to general anaesthesia were protective [186, 187]. There are a number of procedures specific to the abdomen and pelvis that are associated with an increased risk of chronic pain post-surgery including bariatric procedures, inguinal hernia repair, vasectomy, hysterectomy and caesarean section. The estimated prevalence of CPSP following bariatric surgery is 30% [188]. In affected individuals careful assessment that may include laparoscopy could identify a treatable cause (such as adhesions, mesenteric defect or cholecystitis) and lead to a significant reduction in post-operative pain [189]. Inguinal hernia repair can lead to CPSP in up to 10% of patients at 6 months [164] and may present with groin and/or scrotal pain. The incidence of post vasectomy pain ranges from 2-20% [159, 160]. The risk is significantly lower following the no scalpel technique [161]. The incidence of post-surgical pain following hysterectomy is difficult to determine as pain is a common indication for the operation. When defined as CPSP, rates are estimated at 28-30% [190, 191]. Careful case selection and management of patient expectation is therefore important. The frequency of caesarean section has increased over time. A meta-analysis has shown a significant incidence of CPSP both at three months and at more than 12 months (15% and 11% respectively) [192], therefore careful counselling is needed in non-emergency cases. 3.2.5.8 Associated conditions in pelvic pain syndromes Nerve damage Spinal pathology and any pathology along the course of the nerve involved may result in neuropathic pain in

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the distribution of these nerves. Neoplastic disease, infection, trauma, surgical incisions and post-operative scarring may result in nerve injury [193]. Pudendal neuralgia is the most often mentioned form of nerve damage in the literature. Anatomical variations may pre-dispose the patient to developing pudendal neuralgia over time or with repeated low-grade trauma (such as sitting for prolonged periods of time or cycling) [194, 195]. The pudendal nerve may be damaged at the level of: 1. The piriformis muscle. For example, as part of a piriformis syndrome: in some cases, the nerve may pass through the muscle and hence be trapped; or in other cases, muscle hypertrophy or spasm is implicated. 2. The sacrospinal/sacrotuberous ligaments, possibly accounting for 42% of cases. 3. Within Alcock’s canal (medial to the obturator internus muscle, within the fascia of the muscle), possibly accounting for 26% of cases. 4. Multiple levels in 17% of cases. The site of injury determines the location of perceived pain and the nature of associated symptoms (e.g., the more distal the damage, the less likely the anal region will be involved). The clinical presentation depends on different factors. There is a wide age range, as one would expect, with a condition that has so many potential causes. It is suggested that, the younger the patient, the better the prognosis. Essentially, the sooner the diagnosis is made, as with any compression nerve injury, the better the prognosis, and older patients may have a more protracted problem [196, 198]. Six out of ten cases are observed in women. Some special situations can be listed: • In orthopaedic hip surgery, pressure from the positioning of the patient, where the perineum is placed hard against the brace, can result in pudendal nerve damage [199, 200]. The surgery itself may also directly damage the nerve. Pelvic surgery such as sacrospinous fixation is clearly associated with pudendal nerve damage in some cases [201, 202]. In many types of surgery, including colorectal, urological and gynaecological, pudendal nerve injury may be implicated. • Fractures of the sacrum or pelvis may result in pudendal nerve/root damage and pain. Falls and trauma to the gluteal region may also produce pudendal nerve damage if associated with significant tissue injury or prolonged pressure. • Tumours in the pre-sacral space must be considered. Tumours invading the pudendal nerve may occur and there may also be damage from surgery for pelvic cancer [203]. • The pudendal neuralgia of birth trauma is thought to resolve in most cases over a period of months. However, rarely, it appears to continue as painful neuropathy. Multiple pregnancies and births may predispose to stretch neuropathy in later life. This is more difficult to be certain about [204]. • Child birth and repeated abdominal straining associated with chronic constipation [205] are thought to pre-dispose elderly women to post-menopausal pelvic floor descent and stretching of the pudendal nerve with associated pain. Changes in the hormone status may also be a factor. In Urogenital Pain Management Centres, the commonest associations with pudendal neuralgia appear to be: history of pelvic surgery; prolonged sitting (especially young men working with computer technology); and postmenopausal older women. Sexual dysfunction Chronic pelvic pain is a clinical condition that results from complex interactions of physiological and psychological factors and has a direct impact on the social, personal and professional lives of men and women. Men Chronic pain as well as its treatment can impair our ability to express sexuality. In a study in England, 73% of patients with any chronic pain had some degree of sexual problems as a result of the pain [124]. These problems can occur because of several factors. Psychological factors like decrease in self-esteem, depression and anxiety can contribute to loss of libido. Physiological factors like fatigue, nausea and pain itself can cause sexual dysfunction. Pain medications (opioids, and the selective serotonin re-uptake inhibitors [SSRIs]) can also decrease libido [206] and delay ejaculation. The number of studies on the effects of CPPPS on sexual function is limited. Sexual dysfunction is often ignored because of a lack of standardised measurements. At present, the most commonly used tool is the IIEF questionnaire [146]. The presence of pelvic pain may increase the risk for ED independent of age [207]. On the other hand, crosssectional data suggest no improvement of lower urinary tract symptoms (LUTS) by an increased frequency of ejaculation [208]. Although mental distress and impaired QoL related to illness could contribute to sexual dysfunction observed in patients with PPPS, the presence of erectile and ejaculatory disorders is more

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frequently related to symptoms suggestive of a more severe inflammatory condition [118]. These arguments are important for the understanding of the close relationship between CPPPS symptoms, disturbed sexuality, impact on QoL, and psychological implications including depression and more failure anticipation thoughts, [108-110, 208-210]. Sexual dysfunction heightens anger, frustration and depression, all of which place a strain on the patients’ relationships. The female partners of men with sexual dysfunction and depression often present with similar symptoms including pain upon intercourse and depressive symptoms. Men with CPPPS have reported a high frequency of sexual relationship dissolution and psychological symptoms, such as depression and suicidal thinking [108, 211]. Primary Prostate Pain Syndrome patients reported substantial sexual and relationship problems [108, 211]. On the other hand, it was found that men with PPPS did not report significantly decreased sexual satisfaction compared to controls [212]. There is consensus that therapeutic strategies reducing symptoms of pelvic pain are of relevance in relation to changes in sexual function. Also intimacy and having sex can yield positive experiences that will reduce the pain. The CNS plays an important role in this mechanism. Women Chronic pelvic pain leads to substantial impairment in QoL and several sexual dysfunctions [120, 213-215]. It seems reasonable to expect that pain, extreme fatigue, depressive mood and pain drugs will affect women’s sexuality. Women with CPPPS reported significantly more pain, depression, and anxiety symptoms and were physically more impaired than women in the control group. In comparison with controls, women with CPPPS reported significantly more sexual avoidance behaviour, non-sensuality, and complaints of “vaginismus” [216]. Patients with CPPPS reported more sexual problems than women with any other type of chronic pain problem [217]. The quality of intimate relationships is closely connected with sexual function [218]. Satisfaction with sexual relationships appears to be associated with higher marital functioning [219]. In addition sexual dissatisfaction is related to sexual dysfunction. When one partner suffers from chronic pain, the ability of both partners to cope with the pain and the extent to which partners are supportive of the chronic pain sufferer have been found to be a predictor of sexual functioning [219]. Approximately two-thirds of patients in another study reported reduced frequency in their sexual relations as a result of CPPPS [220]. One study demonstrated that CPPPS patients reported worse sexual function with regard to desire, arousal, lubrication, orgasm, satisfaction, and more frequent and severe pain with vaginal penetration than women without CPPPS [221]. In an interview with 50 chronic pain sufferers and their spouses, 78% of the pain sufferers and 84% of partners described deterioration, including cessation of their sex life [222]. In a study in patients with back pain, half reported decreased frequency of sex since the onset of chronic pain [124]. The Female Sexual Function Index (FSFI) has been developed as a brief, multi-dimensional self-report instrument for assessing the key dimensions of sexual function in women, which includes desire, subjective arousal, lubrication, orgasm, satisfaction, and pain. Using the FSFI, women with CPPPS reported worse sexual function in all subscales and total score than women without CPPPS. The largest differences between women with CPPPS and without CPPPS were seen for the domains of pain and arousal. The total score and the subscales of the FSFI had high levels of internal consistency and test-retest reliability when assessed in a sample of women with CPPPS. The FSFI also showed good ability to discriminate between women with and without CPPPS [221]. Myofascial pain Myalgia is too often overlooked as a form of chronic pelvic pain. The pelvic floor and adjacent muscles are used in an abnormal way. Studies in the field of chronic prostatitis support the idea that patients with CPPPS have more muscle spasm and increased muscle tone and report pain when the pelvic floor muscles are palpated [223]. Learning pelvic floor muscle relaxation can diminish spasm and pain [224]. Repeated or chronic muscular overload can activate trigger points in the pelvic floor muscles. A report from the Chronic Prostatitis Cohort Study showed that 51% of patients with prostatitis and only 7% of controls had any muscle tenderness. Tenderness in the pelvic floor muscles was only found in the CPPPS group [129]. The first ideas about the neurological aspects of the pelvic floor muscles in relation to chronic pelvic pain were published in 1999. The possibility of CNS changes in the regulation of pelvic floor function was suggested as a mechanism for development of CPPPS. Of the patients presenting with pelvic pain, 88% had poor to absent pelvic floor muscle function [128]. Animal studies on the role of neurogenic inflammation have also elucidated some important phenomena. Irritation of the prostate, bladder and pelvic floor muscles results in expression of C-fos-positive cells in the CNS. There appears to be convergence of afferent information onto central pathways. Once the central changes have become established, they become independent of the peripheral input that initiated them [225].

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Repeated or chronic muscular overload can activate trigger points in the muscle. Trigger points are defined as hyper-irritable spots within a taut band. Other criteria for trigger points are recognition of the pain as ‘familiar’, and pain on stretching the muscle. Apart from pain, trigger points prevent full lengthening of the muscle, thereby restricting the range of movement. Pain as a result of these trigger points is aggravated by specific movements and alleviated by certain positions. Positions and movements in which the shortened muscle is stretched are painful. Patients know which activities and postures influence pain. Trigger points can be located within the pelvic floor muscles and in adjacent muscles such as the abdominal, gluteal and iliopsoas muscles. Pain is aggravated by pressure on the trigger point (e.g., pain related to sexual intercourse). Pain also worsens after sustained or repeated contractions of pelvic floor muscles (e.g., pain related to voiding or defecation).

3.3

Abdominal aspects of pelvic pain

3.3.1 Incidence Epidemiological data on IBS and CPPPS are scarce [226]. Chronic Pelvic Pain has been shown to be one of the most common functional disorders in women of reproductive age. The monthly incidence rate of CPPPS published by Zondervan et al. was 1.58/1000 [227]. 3.3.2 Prevalence Using a vague definition of continuous or episodic pain situated below the umbilicus over six months, one study reported that CPPPS was one of the most common diagnoses in primary care units in Great Britain [227]. The monthly prevalence rate of CPPPS in this study was 21.5/1,000, with an annual prevalence of 38.3/1,000. The prevalence rates increase significantly with older age and vary significantly between regions in the UK. The overall prevalence of anorectal pain in a sample of USA householders was 6.6% and was more common in women [228]. Irritable bowel syndrome is associated with common gynaecologic problems (endometriosis, dyspareunia, and dysmenorrhoea) [229]. Fifty per cent of women who presented with abdominal pain to the gynaecologic clinic or were scheduled for laparoscopy due to CPPPS had symptoms of IBS [230]. In a survey from Olmsted county 20% of women reported CPPPS and 40% of those met criteria for IBS [22]. This overlap of CPPPS and IBS was associated with an increased incidence of somatisation. Not gynaecological surgical procedures but only psychosocial variables predict pain development without a different incidence of IBS in a prospective and controlled study [231]. Clinical features of pelvic floor dysfunction, gynaecological and psychological features are related to disordered anorectal function in IBS patients but do not predict physiological anorectal testing. 3.3.3 Influence on QOL There is little known on health related quality of life (HRQoL) in patients with CPPPS. There is a need to develop validated disease specific HRQoL instruments for CPPPS in addition to sound measurement properties. More data are available in patients with IBS treated at referral centres who have comparable HRQoL scores as patients with other common disorders such as diabetes, end-stage renal disease, and inflammatory bowel disease [232]. Sub-groups of IBS with predominance of diarrhoea or constipation show no difference in HRQoL. Multi-variate analysis shows that HRQoL in patients with IBS is affected by sex and psychological conditions. 3.3.4 Costs Costs combine direct health-care costs and societal costs (productivity loss) such as under-performance and absenteeism from work. The annual costs to society can be calculated by using the average population earnings. In Germany direct care costs are estimated at €791 and societal costs €995 per patient with IBS per year which may be comparable to patients with CPPPS [233]. 3.3.5 Risk factors & underlying causes Risk factors are covered in Section 3.1.5.

3.4

Summary of evidence and recommendations: CPPPS and mechanisms

Summary of evidence CPPPS mechanisms are well defined and involve mechanisms of neuroplasticity and neuropathic pain. The mechanisms of neuroplasticity and neuropathic pain result in increased perception of afferent stimuli which may produce abnormal sensations as well as pain. End-organ function can also be altered by the mechanisms of neuroplasticity so that symptoms of function can also occur. The diagnosis of a CPPPS as a pain syndrome is essential as it encourages a holistic approach to management with multi-specialty and multi-disciplinary care.

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Recommendations All of those involved in the management of chronic pelvic pain should have knowledge of peripheral and central pain mechanisms. The early assessment of patients with chronic pelvic pain should involve investigations aimed at excluding disease-associated pelvic pain. Assess functional, emotional, behavioural, sexual and other quality of life issues, such as effect on work and socialisation, early in patients with chronic pelvic pain and address these issues as well as the pain. Build up relations with colleagues so as to be able to manage chronic pelvic primary pain syndrome comprehensively in a multi-specialty and multi-disciplinary environment with consideration of all their symptoms.

4.

DIAGNOSTIC EVALUATION

4.1

General Evaluation

Strength rating Strong Strong Strong

Strong

4.1.1 History History is very important for the evaluation of patients with chronic pelvic pain. Pain syndromes are symptomatic diagnoses, which are derived from a history of pain perceived in the region of the pelvis, and absence of other pathology, for a minimum of three months. This implies that specific disease-associated pelvic pain caused by bacterial infection, cancer, drug-induced pathology (e.g., ketamine use) [234], primary anatomical or functional disease of the pelvic organs, and neurogenic disease must be ruled out. 4.1.1.1 Anxiety, depression, and overall function Distress is best understood in the context of pain and of the meaning of pain to the individual and is best assessed ideographically rather than normatively. Almost all diagnostic measures and standardised instruments of anxiety and depression are designed for people without significant physical problems, so are difficult to interpret in chronic pelvic pain [235]. Anxiety about pain often refers to fears of missed pathology (particularly cancer) as the cause of pain [34], or to uncertainties about treatment and prognosis. These can drive healthcare seeking behaviour. The question: “What do you believe or fear is the cause of your pain?” has been suggested [236]. Anxiety may also concern urinary urgency and frequency that are problematic in social settings. Depression or depressed mood are common in chronic pain [237] e.g., often related to losses consequent to chronic pain (work, leisure activities, social relationships, etc.). Due to the lack of suitable assessment instruments, it is better to ask a simple question such as “How does the pain affect you emotionally?” If the answer gives cause for concern about the patient’s emotional state, further assessment should be undertaken by an appropriately qualified colleague. Most measures of restricted function are designed primarily for musculoskeletal pain and may emphasise mobility problems rather than the difficulties of the individual with pelvic or urogenital pain. A promising specific measure, UPOINT, was introduced and in a later version the sexological aspects were added [238]. However, it may underassess relevant psychological variables [43]. Generic QoL measures are helpful. If such an instrument is not already used in the clinic, the Brief Pain Inventory [239] provides a broad and economical assessment of interference of pain with various aspects of life in multiple languages. (For further suggested instruments see [240]). In a study, more pain, pain-contingent rest, and urinary symptoms were associated with poorer function [58]. 4.1.1.2 Urological aspects Pain may be associated with urological symptoms. A detailed history of lower urinary tract functions should be taken. Dysfunctions of the lower urinary tract may exacerbate symptoms, as pain may interfere with the function of the lower urinary tract. Micturition in all its aspects should be addressed. Special attention should be paid to the influence of micturition on the experience of pain. Primary prostate pain syndrome Primary prostate pain syndrome is diagnosed from a history of pain perceived in the region of the prostate (convincingly reproduced by prostate palpation), and absence of other lower urinary tract pathology, for a minimum of three months. As mentioned above, specific disease-associated pelvic pain must be ruled

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out. A thorough history is an important first step in the evaluation of PPPS. It should include type of pain and localisation. Pain is often reported in other pelvic areas outside the prostate such as perineum, rectum, penis, testicles and abdomen [50]. In addition, associated lower urinary tract symptoms, sexual function, psychological, social and economic factors should be addressed. Determination of the severity of disease, its progression and treatment response can be assessed only by means of a validated symptom-scoring instrument (see Section 4.2.3). These subjective outcome measures are recommended for the basic evaluation and therapeutic monitoring of patients in urological practice. Primary bladder pain syndrome Primary bladder pain syndrome should be diagnosed on the basis of pain, pressure or discomfort associated with the urinary bladder, accompanied by at least one other symptom, such as daytime and/or night-time increased urinary frequency, the exclusion of confusable diseases as the cause of symptoms, and if indicated, cystoscopy with hydrodistension and biopsy (Table 4) [15]. The nature of pain is key to disease definition: 1. pain, pressure or discomfort perceived to be related to the bladder, increasing with increasing bladder content; 2. located suprapubically, sometimes radiating to the groins, vagina, rectum or sacrum; 3. relieved by voiding but soon returns [241, 242]; 4. aggravated by food or drink [242]. Primary bladder pain syndrome type 3 can lead to a small capacity fibrotic bladder with or without upper urinary tract outflow obstruction. 4.1.1.3 Gynaecological aspects A detailed medical history outlining the nature, frequency and site of pain; its relationship to precipitating factors and the menstrual cycle, may help define the aetiology. A menstrual and sexual history, including a history of sexually transmitted diseases, vaginal discharge, as well as previous sexual trauma is mandatory as well as up to date cervical cancer screening. A history of obstetric and/or gynaecological surgery is also warranted, particularly if devices such as synthetic mesh were used. 4.1.1.4 Gastrointestinal aspects The predominant symptoms that patients are interviewed about are discomfort or pain in relation to their bowel habits, daily activities, and eating. A precise history of dysfunctional voiding or defecation should be asked, ideally applying symptom questionnaires for urinary and anorectal symptoms (e.g., Rome III criteria for anorectal pain). Excessive straining at most defecations, anal digitations in dyssynergic defecation, and a sensation of anal blockage may be found in patients with chronic anal pain. History of anxiety and depression with impaired QoL is often encountered in anorectal functional disorders and should be evaluated. Diagnostic criteria for primary chronic anal pain syndrome (chronic proctalgia) according to the Rome III criteria are as follows and must include all of the following: chronic or recurrent rectal pain or aching, episodes last at least 20 minutes and exclusion of other causes of rectal pain such as ischaemia, inflammatory bowel disease, cryptitis, intramuscular abscess and fissure, haemorrhoids, prostatitis, and Coccyx Pain Syndrome. These criteria should be fulfilled for the past three months with symptom onset at least six months before diagnosis [243, 244]. The primary chronic anal pain syndrome includes the above diagnostic criteria and exhibits exquisite tenderness during posterior traction on the puborectalis muscle (previously called “Levator Ani Syndrome”). Pathophysiology of pain is thought to be due to over-activity of the pelvic floor muscles. Primary intermittent chronic anal pain syndrome (proctalgia fugax) consists of all the following diagnostic criteria, which should be fulfilled for three months: recurrent episodes of pain localised to the anus or lower rectum, episodes last from several seconds to minutes and there is no anorectal pain between episodes. Stressful life events or anxiety may precede the onset of the intermittent chronic anal pain syndrome. The attacks may last from a few seconds to as long as 30 minutes. The pain may be cramping, aching or stabbing and may become unbearable. However, most patients do not report it to their physicians and pain attacks occur less than five times a year in 51% of patients. 4.1.1.5 Peripheral nerve aspects A proportion of patients will be able to relate the onset of pain to an acute event such as surgery, sepsis or trauma, and occasionally, cycling for a prolonged period. Chronic injury is more frequent, such as associated with sitting for prolonged periods over time. Many will be idiopathic.

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The pain is classically perceived in the perineum from anus to clitoris/penis. However, less-specific pain distribution may occur, and this may be due to anatomical variation, involvement of branches of the nerve rather that the main nerve, CNS central sensitisation, and consequently, the involvement of other organs and systems in a regional pain syndrome. Other nerves in the vicinity may also be involved, for example, inferior cluneal nerve and perineal branches of the posterior femoral cutaneous nerve. The musculoskeletal system may become involved, confusing the pain picture as aches and pain developing in the muscles due to immobility and disability, possibly magnified by the CNS changes. Burning is the most predominant adjective used to describe the pain. Crushing and electric may also be used, indicating the two components - a constant pain often associated with acute sharp episodes. Many patients may have the feeling of a swelling or foreign body in the rectum or perineum, often described as a golf or tennis ball. The term pain has different meanings to patients and some would rather use the term discomfort or numbness. Aggravating factors include any type of pressure being applied, either directly to the nerve or indirectly to other tissue, resulting in pudendal traction. Allodynia is pain on light touch due to involvement of the CNS, and may make sexual contact and the wearing of clothes difficult. These patients often remain standing, and as a consequence, develop a wide range of other aches and pains. Soft seats are often less well-tolerated, whereas sitting on a toilet seat is said to be much better tolerated. If unilateral, sitting on one buttock is common. The pain may be exacerbated by bowel or bladder evacuation. Pudendal nerve damage may be associated with a range of sensory phenomena. In the distribution of the nerve itself, as well as unprovoked pain; the patient may have paraesthesia (pins and needles); dysaesthesia (unpleasant sensory perceptions usually but not necessarily secondary to provocation, such as the sensation of running cold water); allodynia (pain on light touch); or hyperalgesia (increased pain perception following a painful stimulus, including hot and cold stimuli). Similar sensory abnormalities may be found outside of the area innervated by the damaged nerve, particularly for visceral and striated muscle hyperalgesia. The cutaneous sensory dysfunction may be associated with superficial dyspareunia, but also irritation and pain associated with clothes brushing the skin. There may also be a lack of sensation and pain may occur in the presence of numbness. Visceral hypersensitivity may result in an urge to defecate or urinate. This is usually associated with voiding frequency, with small amounts of urine being passed. Pain on visceral filling may occur. Anal pain and loss of motor control may result in poor bowel activity, with constipation and/or incontinence. Ejaculation and orgasm may also be painful or reduced. Many of those suffering from pudendal neuralgia complain of fatigue and generalised muscle cramps, weakness and pain. Being unable to sit is a major disability, and over time, patients struggle to stand and they often become bedbound. The immobility produces generalised muscle wasting, and minimal activity hurts. As a consequence of the widespread pain and disability, patients often have emotional problems, and in particular, depression. Patients with chronic pelvic pain are also often anxious and have the tendency to catastrophise. Depression, catastrophising and disability are all poor prognostic markers. Cutaneous colour may change due to changes in innervation but also because of neurogenic oedema. The patient may describe the area as swollen due to this oedema, but also due to the lack of afferent perception. 4.1.1.6 Myofascial aspects When taking a history from a patient with pelvic pain, it is important to address the function of all the organs in the pelvic area. The following items certainly should be addressed: lower urinary tract function, anorectal function, sexual function, gynaecological items, presence of pain and psychosocial aspects. One cannot state that there is a pelvic floor dysfunction based only on the history. But there is a suspicion of pelvic floor muscle dysfunction when two or more pelvic organs show dysfunction, for instance a combination of micturition and defecation problems. 4.1.2 Physical Evaluation The clinical examination often serves to confirm or refute the initial impressions gained from a good history. The examination should be aimed at specific questions where the outcome of the examination may change management. Prior to an examination, best practice requires the medical practitioner to explain what will happen and what the aims of the examination are to the patient. Consent to the examination should occur during that discussion and should cover an explanation around the aim to maintain modesty as appropriate and, if necessary, why there is a need for rectal and/or vaginal examination. Finally, the risk of exacerbating the pain should form a part of that request. A record of the discussion should be noted. The possibility of

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the presence of a chaperone should be discussed with the patient. As well as a local examination, a general musculoskeletal and neurological examination should be considered an integral part of the assessment and undertaken. Following the examination, it is good practice to ask the patient if they had any concerns relating to the conduct of the examination and that discussion should be noted. There is no specific diagnostic test for CPPPS, therefore, procedures are on the one hand directed towards identification and exclusion of specific diseases associated with pelvic pain, and on the other hand may be used for phenotypic description. Abdominal and pelvic examination to exclude gross pelvic pathology, as well as to demonstrate the site of tenderness is essential. It is important to look for abnormalities in muscle function. Examination of the external genitalia is a part of the evaluation. In patients with scrotal pain, gentle palpation of each component of the scrotum is performed to search for masses and painful spots. The penis and urethra may be palpated in a similar way. Many authors recommend that one should assess cutaneous allodynia along the dermatomes of the abdomen (T11-L1) and the perineum (S3), and the degree of tenderness should be recorded. The bulbocavernosus reflex in the male may also provide useful information concerning the intactness of the pudendal nerves. Clinical pelvic examination should be a single digit examination if possible. The usual bi-manual examination can generate severe pain so the examiner must proceed with caution. A rectal examination is done to look for prostate abnormalities in male patients including pain on palpation and to examine the rectum and the pelvic floor muscles regarding muscle tenderness and trigger points as well as the ability to contract and relax these muscles. At clinical examination, perianal dermatitis may be found as a sign of faecal incontinence or diarrhoea. Fissures may be easily overlooked and should be searched for thoroughly in patients with anal pain. A rectal digital examination findings may show high or low anal sphincter resting pressure, a tender puborectalis muscle in patients with the Levator Ani Syndrome, and occasionally increased perineal descent. The tenderness during posterior traction on the puborectalis muscle differentiates between Levator Ani Syndrome and unspecified Functional Anorectal Pain and is used in most studies as the main inclusion criterion. Dyssynergic (paradoxical) contraction of the pelvic muscles when instructed to strain during defecation is a frequent finding in patients with pelvic pain. Attention should be paid to anal or rectal prolapse at straining, and ideally during combined rectal and vaginal examination to diagnose pelvic organ prolapse. A full clinical examination of the musculo-skeletal, nervous and urogenital systems is necessary to aid in diagnosis of pudendal neuralgia, especially to detect signs indicating another pathology. Often, there is little to find in pudendal neuralgia and frequently findings are non-specific. The main pathognomonic features are the signs of nerve injury in the appropriate neurological distribution, for example, allodynia or numbness. Tenderness in response to pressure over the pudendal nerve may aid the clinical diagnosis. This may be elicited by per rectal or per vaginal examination and palpation in the region of the ischial spine and/or Alcock’s canal. Muscle tenderness and the presence of trigger points in the muscles may confuse the picture. Trigger points may be present in a range of muscles, both within the pelvis (levator ani and obturator internus muscles) or externally (e.g., the piriformis, adductors, rectus abdominis or paraspinal muscles).

4.2

Supplemental evaluation

If history is suggestive of lower urinary tract, gynaecological, anorectal or other disease of known aetiology, diagnostic work-up should follow respective guidelines. 4.2.1 Assessing pelvic pain and related symptoms Determination of the severity of pain and associated symptoms, its progression and treatment response can be assessed only by means of a reliable and validated symptom-scoring instrument. These subjective outcome measures are recommended for the basic evaluation and therapeutic monitoring of patients. Pain should always be assessed at presentation and (see below) to identify progression and treatment response. As well as doing this in the clinic, the patient can keep a daily record (pain diary). This may need to include other relevant variables such as voiding, sexual activity, activity levels, or analgesic use. Increased attention to patient reported outcomes gives prominence to patients’ views on their disease and pain diaries, in patients’ own environments, improve data quality. Quality of life should also be measured because it can be very poor compared to other chronic diseases [245, 246]. In a study more pain, pain-contingent rest, and urinary symptoms were associated with greater disability (also measured by self-report), and pain was predicted by depression and by catastrophising (helplessness subscale) [58].

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Where the primary outcome of treatment is pain relief, it is useful before starting treatment to agree a clinically useful level of relief [247]. The most reliable methods are: • a five point verbal scale: none, mild, moderate, severe, very severe pain; • a VAS score from one to ten; • an eleven point numerical scale (as below).

An 11 point numerical scale

Pain assessment ratings are not independent of cognitive and emotional variables [57]. Target outcomes of pain severity, distress and disability co-vary only partly, and improvement in one does not necessarily imply improvement in the others. When the primary outcome is pain its meaning should be anchored in discussion of clinically important difference [247]. Primary prostate pain syndrome Reliable, valid indices of symptoms and QoL are the NIH-CPSI [248] and the International Prostate Symptom Score (I-PSS) [249]. Primary bladder pain syndrome Symptom scores may help to assess the patient and act as outcome measures. The O’Leary-Sant Symptom Index, also known as the Interstitial Cystitis Symptom Index (ICSI) was validated in a large study [250]. Gastrointestinal questionnaire Functional anorectal pain disorders (anorectal pelvic pain) are defined and characterised by duration, frequency, and quality of pain. More complex questionnaires are used in the setting of IBS. The validated IBSSymptom Severity Scale (IBS-SSS) includes the broadest measurement of pain-related aspects [251, 252]. However, as different instruments measure different endpoints of chronic abdominal pain in IBS, a comparison of published studies is often impossible. Sexual function assessment In males the most frequent effects on sexual function are ED and premature ejaculation. These can be evaluated by proper questionnaires namely IIEF and PEDT (Premature Ejaculation Diagnostic Tool). In comparison with controls, women with chronic pelvic pain reported significantly more sexual avoidance behaviour, non-sensuality, and complaints of “vaginismus” [205]. The Female Sexual Function Index (FSFI) has been developed as a brief, multi-dimensional self-report instrument for assessing the key dimensions of sexual function in women, which includes desire, subjective arousal, lubrication, orgasm, satisfaction, and pain. The corresponding evidence in men is lacking. 4.2.2 Focused myofascial evaluation Pelvic floor muscle testing can be done by the medical doctor but a consultation of the pelvic floor by a physiotherapist is a good alternative, but either should have had appropriate training in pelvic assessment. A vaginal or rectal examination is performed to assess the function of the pelvic floor muscles, according to the International Continence Society (ICS) report. This assessment has been tested and shows satisfactory validity and intra-observer reliability. It can therefore be considered suitable for use in clinical practice [253]. Rectal examination is a good way to test the pelvic floor function in men [254]. There is a growing number of reports on the use of ultrasound (US) in establishing the function of the pelvic floor muscles. The exact place in the diagnostic setting needs to be addressed in the future [255]. In a cohort study of 72 men with chronic pelvic pain, the relationship between the locations of the trigger point and the referred pain was examined. Ninety percent of the patients showed tenderness in the puborectalis muscle and 55% in the abdominal wall muscles. Of the patients in whom trigger points were found in the puborectalis, 93% reported pain in the penis and 57% in the suprapubic region. Patients with trigger points in the abdominal muscles reported pain in the penis (74%), perineum (65%) and rectum (46%) [256]. In addition, a broad musculoskeletal (tender point) evaluation, including muscles outside the pelvis, helps to diagnose the myofascial pain aspects of the pelvic pain in phenotyping pelvic pain patients [257, 258]. 4.2.3

Neurological

Injections An injection of local anaesthetic and steroid at the site of nerve injury may be diagnostic. Differential block

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of the pudendal nerve helps to provide information in relation to the site where the nerve may be trapped [259, 260]. Infiltration at the ischial spine requires the use of a nerve stimulator/locator. Both motor (anal contraction) and sensory endpoints may be noted. The anatomical target may be localised by fluoroscopy, computed tomography (CT) guidance, or the use of US. Ultrasound avoids any form of radiation, whereas CT guidance involves a significant amount of radiation. Currently, fluoroscopy is probably the imaging technique most frequently used because it is readily available to most anaesthetists that perform the block. Currently, infiltration of the pudendal nerve within Alcock’s canal is primarily undertaken with the use of CT. As well as injecting around the pudendal nerve, specific blocks of other nerves arising from the pelvis may be performed. Electrophysiological studies These may reveal signs of perineal denervation, increased pudendal nerve latency, or impaired bulbocavernosus reflex [196, 199, 261-263]. However, for an abnormality to be detected, significant nerve damage is probably necessary. Pain may be associated with limited nerve damage, therefore, these investigations are often normal. 4.2.4 Imaging Ancillary studies should be performed according to appropriate guidelines for exclusion of diseases with known aetiology presenting with symptoms identical to those of CPPS. Once the latter diagnosis is established, studies can be useful to assess functional abnormalities and phenotype conditions such as PBPS, and primary chronic anal pain syndrome. Ultrasound Ultrasound has limited value but may reassure patients. However, over-investigating may be detrimental. MRI Magnetic resonance neurography has been increasingly used in specialised centres for the diagnosis of the location (proximal vs. peripheral) and degree (total vs. partial) of nerve injury in the peripheral nervous system, earlier and with higher specificity than conduction studies. This may show benefits for CPPPS in the coming years. MR defecating proctogram Magnetic resonance imaging in conjunction with MR defecography has become the most valuable imaging technique to assess anorectal function dynamically. Magnetic resonance imaging studies simultaneously outline the anatomy of the pelvic floor and visualise different structural and functional pathologies, by applying dynamic sequences after filling of the rectum with a viscous contrast medium (e.g., US gel). The following pathologies can be visualised: pelvic floor descent, an abnormal anorectal angle while squeezing and straining, rectal intussusception, rectocele, enterocele and cystocele. However, limitations of MR defecography are the left lateral position and the limited space for the patient, which may reduce the ability to strain and thereby reduce the sensitivity of the method, underestimating the size of entero- and rectoceles as well as the amount of intussusception. Functional neuroimaging Functional neuroimaging, functional magnetic resonance imaging (fMRI) is currently being re-evaluated as a research tool and some groups have raised issues around over interpretation [264]. With regards to pain, fMRI findings may represent a pain matrix or may represent non-specific threat processing [265]. Currently this panel cannot recommend fMRI as a clinical tool. 4.2.5

Laboratory Tests

Microbiology tests Primary prostate pain syndrome Laboratory diagnosis of prostatitis has been classically based on the four-glass test for bacterial localisation [266]. Besides sterile pre-massage urine (voided bladder urine-2), PPPS shows < 103 cfu/mL of uropathogenic bacteria in expressed prostatic secretions and insignificant numbers of leukocytes or bacterial growth in ejaculates. However, this test is too complex for use by practising urologists. Diagnostic efficiency may be enhanced cost-effectively by a simple screening procedure, that is, the two-glass test or pre-post-massage test (PPMT) [267, 268]. Overall, these tests help only a little in the diagnosis of PPPS, because 8% of patients with suggested PPPS have been found to have positive prostatic localisation cultures, similar to the percentage of asymptomatic men [269].

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Primary bladder pain syndrome Urine dipstick and urine culture (including culture for Tuberculosis if sterile pyuria) are recommended in all patients suspected of having PBPS. Urine cytology is also recommended in risk groups. Gynaecological aspects of chronic pelvic pain Vaginal and endocervical swabs to exclude infection are recommended. In specific cases, imaging may be required to help rule out a defined pathology such as sacral neuropathy in endometriosis [270]. 4.2.6

Invasive tests

Anorectal pain Anorectal manometry with sensory testing (pressure volume measurement: barostat) may be useful to diagnose dyssynergic defecation and hypersensitivity of the rectum which are typical for patients with CPPPS and IBS. Flexible rectosigmoidoscopy or colonoscopy should be considered in patients with anorectal pain to rule out coincidental colorectal pathology. Laparoscopy for females Laparoscopy is perhaps the most useful invasive investigation to exclude gynaecological pathology [271, 272] and to assist in the differential diagnosis of CPPPS in women [273]. Often, it is combined with cystoscopy [274, 275] and/or proctoscopy to help identify the site of multi-compartment pain. Psychological considerations around laparoscopy Three very different studies of laparoscopy suggest that it can improve pain through resolving concerns about serious disease [276], although showing women the photograph of their pelvic contents did not improve pain on explanation alone [277]. Integrating somatic and psychological assessment from the start rather than dealing with psychological concerns only after excluding organic causes of pelvic pain is helpful [278]. Cystoscopy and bladder biopsy Despite controversy on the diagnostic and follow-up value of cystoscopy in PBPS [279-283], the panel believes that objective findings are important for diagnosis, prognosis and ruling out other treatable conditions (a standardised scheme of diagnostic criteria will also contribute to uniformity and comparability of different studies) [284]. Endoscopically, PBPS type 3 displays reddened mucosal areas often associated with small vessels radiating towards a central scar, sometimes covered by a small clot or fibrin deposit - the Hunner's lesion [241]. The scar ruptures with increasing bladder distension, producing a characteristic waterfall type of bleeding. There is a strong association between PBPS type 3 and reduced bladder capacity under anaesthesia [285]. Non-lesion disease displays a normal bladder mucosa at initial cystoscopy. The development of glomerulations after hydrodistension is considered to be a positive diagnostic sign although they can be observed without PBPS [286]. Biopsies are helpful in establishing or supporting the clinical diagnosis of both classic and non-lesion types of the disease [140, 166, 284, 287, 288]. Important differential diagnoses to exclude, by histological examination, are carcinoma in situ and tuberculous cystitis. Table 4: E  SSIC classification of PBPS types according to results of cystoscopy with hydrodistension and biopsies [15]

Biopsy Not done Normal Inconclusive Positivec

Cystoscopy with hydrodistension Not done Normal

Glomerulationsa

Hunner's lesionb

XX XA XB XC

2X 2A 2B 2C

3X 3A 3B 3C

1X 1A 1B 1C

aCystoscopy:

glomerulations grade 2-3. per Fall’s definition with/without glomerulations. cHistology showing inflammatory infiltrates and/or detrusor mastocytosis and/or granulation tissue and/or intrafascicular fibrosis. bLesion

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4.3

Diagnostic algorithm

Figure 1: Diagnosing chronic pelvic pain

Chronic Pelvic Pain

Physical examinaon

History

Symptom of a well known disease

yes no

Chronic secondary pelvic pain

Chronic primary pelvic pain syndrome

Organ specific symptoms present

yes

Urology

Gynaecology

Gastroenterology

Neurology

Sexology

Pelvic floor

Phenotype and proceed according to Chronic Pelvic Pain Guideline.

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Figure 2: Phenotyping of pelvic pain - UPOINT classification Phenotyping

Assessment

Urology

Urinary flow, micturion diary, cystoscopy, ultrasound, uroflowmetry.

Psychology

Anxiety about pain, depression and loss of funcon, history of negave sexual experiences.

Organ specific

Ask for gynaecological, gastro-intesnal, ano-rectal, sexological complaints. Gynaecological examinaon, rectal examinaon.

Infecon

Semen culture and urine culture, vaginal swab, stool culture.

Neurological

Ask for neurological complaints (sensory loss, dysaesthesia). Neurological tesng during physical examinaon: sensory problems, sacral reflexes and muscular funcon.

Tender muscle

Palpaon of the pelvic floor muscles, the abdominal muscles and the gluteal muscles.

Sexological

Erecle funcon, ejaculatory funcon, post-orgasmic pain.

4.4

Other painful conditions without a urological cause

Dysmenorrhoea Menstrual pain or ‘dysmenorrhoea’ may be primary or secondary. Primary dysmenorrhoea classically begins at the onset of ovulatory menstrual cycles and tends to decrease following childbirth [273]. Secondary dysmenorrhoea suggests the development of a pathological process, such as endometriosis [272], adenomyosis or pelvic infection, which need to be excluded. Infection In pre-menopausal women, a history of Pelvic Inflammatory Disease (PID) must be excluded. A patient’s sexual history should be taken along with swabs to exclude chlamydia and gonorrhoea infection. Bacterial and viral genital tract pathogens should also be excluded [289], as they can cause severe pelvic/vaginal/vulvar pain [290] and are associated with ulcerating lesions and inflammation, which may lead to urinary retention [291]. If there is any doubt about the diagnosis, laparoscopy may be helpful, as one of the differential diagnoses is endometriosis. Endometriosis and adenomyosis The incidence of endometriosis is rising in the developed world. It has widespread impact on women’s lives [292], with pain more important than physical findings in determining QoL [293]. The precise aetiology is unknown, but an association with infertility is recognised [294]. A diagnosis is usually made when a history of secondary dysmenorrhoea and/or dyspareunia exists. On examination, there is often tenderness in the lateral vaginal fornices, reduced uterine mobility, tenderness in the recto-vaginal septum, and on occasion, adnexal masses. Laparoscopy is the most useful diagnostic tool [295-298]. Adenomyosis is associated with augmented pain during menses [299]. It is diagnosed by an US scan of the uterus, which often shows cystic dilatation of the myometrium [300]. Gynaecological malignancy The spread of gynaecological malignancy of the cervix, uterine body or ovary will cause pelvic pain depending on the site of spread. Injuries related to childbirth Trauma occurring at the time of childbirth may lead to chronic pelvic pain related to the site of injury [298]. Female sexual dysfunction is perhaps the commonest presenting problem [301], though increasingly women are reporting other symptoms such as pelvic girdle pain and other genito-pelvic pain of different aetiology [302]. There is often a transient problem with oestrogen deficiency in the post-partum period and during breastfeeding, which can compound this situation. Denervation of the pelvic floor can similarly compound the situation [303].

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Pain associated with pelvic organ prolapse and prolapse surgery Pelvic organ prolapse is often asymptomatic, unless it is so marked that it causes back pain, vaginal pain and skin excoriation [304]. Prolapse is often a disease of older women, and it is often associated with postmenopausal oestrogen deficiency, which may lead to pain associated with intercourse. Prolapse surgery has entailed the use of non-absorbable mesh (usually in the form of “mesh kits”). Although they may have a role in supporting the vagina, they are also associated with several complications including bladder, bowel and vaginal trauma [305] and neuropathy [306]. Patients need to be fully evaluated and may need specialised imaging, using contrast mediums if necessary, to make a diagnosis of the possible cause of the pain [307-310]. Haemorrhoids Chronic pelvic pain is rare in haemorrhoidal disease because endoscopic and surgical treatment is mostly effective in acute disease. The most frequent aetiology of pain without significant bleeding is thrombosed external haemorrhoids or an anal fissure. Haemorrhoidal pain on defecation associated with bleeding is usually due to prolapse or ulceration of internal haemorrhoids. Anaemia from haemorrhoidal bleeding is rare but may arise in patients on anti-coagulation therapy, or those with clotting disorders. Anal fissure Anal fissures are tears in the distal anal canal and induce pain during and after defecation. The pain can last for several minutes to hours. Persistence of symptoms beyond six weeks or visible transversal anal sphincter fibres define chronicity. Fissures located off the midline are often associated with specific diseases such as Crohn’s disease or anal cancer. Internal anal sphincter spasms and ischaemia are associated with chronic fissures. Proctitis Abdominal and pelvic pain in patients with inflammatory bowel disease and proctitis are often difficult to interpret. Faecal calprotectin may help to differentiate between inflammation and functional pain, to spare steroids. Irritable bowel syndrome Although IBS can be associated with pelvic pain, the panel consider a full discussion of this topic beyond the scope of these guidelines. A number of high quality clinical guidelines address this topic [243, 311].

4.5

Summary of evidence and recommendations: diagnostic evaluation

4.5.1

Diagnostic evaluation - general

Summary of evidence Clinical history and examination are mandatory when making a diagnosis.

Recommendation Take a full history and evaluate to rule out a treatable cause in all patients with chronic pelvic pain.

4.5.2

LE 2a

Strength rating Strong

Diagnostic evaluation of PPPS

Summary of evidence Primary prostate pain syndrome (PPPS) is associated with negative cognitive, behavioural, sexual, or emotional consequences, as well as with symptoms suggestive of lower urinary tract and sexual dysfunction. Primary prostate pain syndrome has no known single aetiology. Pain in PPPS involves mechanisms of neuroplasticity and neuropathic pain. Primary prostate pain syndrome has a high impact on QoL. Depression and catastrophic thinking are associated with more pain and poorer adjustment. The prevalence of PPPS-like symptoms is high in population-based studies (> 2%). Reliable instruments assessing symptom severity as well as phenotypic differences exist.

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LE 2b

3 2a 2b 3 2b 2b

37

Recommendations Adapt diagnostic procedures to the patient. Exclude specific diseases with similar symptoms. Use a validated symptom and quality of life scoring instrument, such as the National Institutes of Health Chronic Prostatitis Symptom Index, for initial assessment and follow-up. Assess primary prostate pain syndrome associated negative cognitive, behavioural, sexual, or emotional consequences, as well as symptoms of lower urinary tract and sexual dysfunctions. 4.5.3

Strength rating Strong Strong Strong

Diagnostic evaluation of primary bladder pain syndrome

Summary of evidence Primary bladder pain syndrome has no known single aetiology. Pain in PBPS does not correlate with bladder cystoscopic or histologic findings. Primary bladder pain syndrome Type 3 C can only be confirmed by cystoscopy and histology. Lesion/non-lesion disease ratios of PBPS are highly variable between studies. The prevalence of PBPS-like symptoms is high in population-based studies. Primary bladder pain syndrome occurs at a level higher than chance with other pain syndromes. Primary bladder pain syndrome has an adverse impact on QoL. Reliable instruments assessing symptom severity as well as phenotypical differences exist. Recommendations Perform general anaesthetic rigid cystoscopy in patients with bladder pain to subtype and rule out confusable disease. Diagnose patients with symptoms according to the EAU definition, after primary exclusion of specific diseases, with primary bladder pain syndrome (PBPS) by subtype and phenotype. Assess PBPS associated non-bladder diseases systematically. Assess PBPS associated negative cognitive, behavioural, sexual, or emotional consequences. Use a validated symptom and quality of life scoring instrument for initial assessment and follow-up. 4.5.4

Strong Strong Strong

LE 2b 2b 2b 1b

LE 2a 2b

Diagnostic evaluation of gynaecological aspects chronic pelvic pain

Summary of evidence Laparoscopy is well-tolerated and does not appear to have negative psychological effects.

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Strong

Diagnostic evaluation of urethral pain syndrome

Summary of evidence Primary urethral pain syndrome may be a part of BPS. Urethral pain involves mechanisms of neuroplasticity and neuropathic pain. 4.5.6

Strength rating Strong

Diagnostic evaluation of scrotal pain syndrome

Summary of evidence The nerves in the spermatic cord play an important role in scrotal pain. Ultrasound of the scrotal contents does not aid in diagnosis or treatment of scrotal pain. Post-vasectomy pain is seen in a substantial number of men undergoing vasectomy. Scrotal pain is more often noticed after laparoscopic than after open inguinal hernia repair. 4.5.5

LE 3 2a 2a 2a 2a 2a 2a 2a

LE 1b

CHRONIC PELVIC PAIN - LIMITED UPDATE MARCH 2021

Recommendations Take a full uro-gynaecological history in those who have had a continence or prolapse nonabsorbable mesh inserted and consider specialised imaging of the mesh. Refer to a gynaecologist if clinical suspicion of a gynaecological cause for pain following complete urological evaluation. Laparoscopy should be undertaken in accordance with gynaecological guidelines. 4.5.7

Strength rating Strong Strong

Diagnostic evaluation of anorectal pain syndrome

Summary of evidence Tenderness on traction is the main criterion of the chronic anal pain syndrome.

Recommendation Anorectal function tests are recommended in patients with anorectal pain.

4.5.8

LE 1a

Strength rating Strong

Diagnostic evaluation of nerves to the pelvis

Summary of evidence Multiple sensory and functional disorders within the region of the pelvis/urogenital system may occur as a result of injury to one or more of many nerves. The anatomy is complex. There is no single aetiology for the nerve damage and the symptoms and signs may be few or multiple. Investigations are often normal. The peripheral nerve pain syndromes are frequently associated with negative cognitive, behavioural, sexual, or emotional consequences. Recommendations Rule out confusable diseases, such as neoplastic disease, infection, trauma and spinal pathology. If a peripheral nerve pain syndrome is suspected, refer early to an expert in the field, working within a multidisciplinary team environment. Imaging and neurophysiology help diagnosis but image and nerve locator guided local anaesthetic injection is preferable. 4.5.9

LE 2 1 2 1

Strength rating Strong Weak Weak

Diagnostic evaluation of sexological aspects in chronic pelvic pain

Summary of evidence Chronic pain can lead to decline in sexual activity and satisfaction and may reduce relationship satisfaction. Men who reported having sexual, physical or emotional abuse show a higher rate of reporting symptoms of CPPPS. Sexual dysfunctions are prevalent in men with PPPS. In men with PPPS the most prevalent sexual complaints are ED and ejaculatory dysfunction. In females with CPPPS all sexual function domains are lower. The most reported dysfunctions are sexual avoidance, dyspareunia and “vaginismus”. Vulvar pain syndrome is associated with PBPS. Women with PBPS suffer significantly more from fear of pain, dyspareunia and decreased desire. Pelvic floor muscle function is involved in the excitement and orgasm phases of sexual response. Chronic pain can cause disturbances in each of the sexual response cycle phases. Recommendation Screen patients presenting with symptoms suggestive for chronic primary pelvic pain syndrome for abuse, without suggesting a causal relation with the pain.

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LE 2a 2b 2b 3 2a 2a 2a 3 2b

Strength rating Weak

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4.5.10

Diagnostic evaluation of psychological aspects of chronic pelvic pain

Summary of evidence There is no evidence that distress generates complaints of pelvic pain, or that multiple symptoms suggest unreality of pain. Current or recent sexual abuse are possible contributory factors in pelvic pain.

Recommendations Assess patient psychological distress in relation to their pain. Ask patients what they think is the cause of their pain and other symptoms to allow the opportunity to inform and reassure. 4.5.11

LE 2b 2a

Strength rating Strong Strong

Diagnostic evaluation of pelvic floor function

Summary of evidence The ICS classification is suitable for clinical practice. Over-activity of the pelvic floor muscles is related to chronic pelvic pain, prostate, bladder and vulvar pain. Over-activity of the pelvic floor muscles is an input to the CNS causing central sensitisation. There is no accepted standard for diagnosing myofascial trigger points. There is a relation between the location of trigger point and the region where the pain is perceived.

LE 2a 2a 2b 2a 3

Recommendations Strength rating Use the International Continence Society classification on pelvic floor muscle function and Strong dysfunction. In patients with chronic primary pelvic pain syndrome, it is recommended to actively look for Weak the presence of myofascial trigger points.

5.

MANAGEMENT

The philosophy for the management of chronic pelvic pain is based on a bio-psychosocial model. This is a holistic approach with the patients’ active involvement. Single interventions rarely work in isolation and need to be considered within a broader personalised management strategy. The management strategy may well have elements of self-management. Pharmacological and nonpharmacological interventions should be considered with a clear understanding of the potential outcomes and end points. These may well include: psychology, physiotherapy, drugs and more invasive interventions. Treatment philosophy Providing information that is personalised and responsive to the patient’s problems, conveying belief and concern, is a powerful way to allay anxiety [312]. Additional written information or direction to reliable sources of information is useful; practitioners tend to rely on locally produced material or pharmaceutical products of variable quality while endorsing the need for independent materials for patients [313].

5.1

Conservative management

5.1.1 Pain education It is always valuable to include education about the causes of pain, including eliciting from patients their anxieties about undiscovered pathology and addressing them. Information improves adherence to treatment and underpins self-management, as shown in many other painful and non-painful disorders but not specifically in pelvic and abdominal pain except by a small qualitative study [314].

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5.1.2 Physical therapy The physiotherapist is part of the pain management team; (including doctors, psychologists and nurses). The therapeutic options for physiotherapists may not be the same in every country. Physiotherapists can either specifically treat the pathology of the pelvic floor muscles, or more generally treat myofascial pain if it is part of the pelvic pain syndrome. In most studies that have been done looking at the effect of physiotherapy in pelvic pain, the treatment of the pelvic floor is only part of the pain management. In a review about physiotherapy in women with pelvic pain, it was concluded that recommendations for physiotherapy should be given with caution [315]. The review found six RCTs, of which three showed level 1b evidence with low-risk of bias. One of these three found that Mensendieck somatocognitive therapy showed a pain reduction after one year followup of 64%. This approach consists of myofascial relaxation and tension, improving posture and movement in combination with cognitive behaviour therapy (CBT) [316]. Pelvic floor muscle pain Treating pelvic floor over-activity and myofascial trigger points should be considered in the management of chronic pelvic pain. Treatment should be done by specialised physiotherapists who are trained not only in the musculo-skeletal aspects of pain, but also in the psychological mechanisms and the role of the CNS in chronic pain. For patients with chronic pelvic pain and dysfunction of the pelvic floor muscles, it is very helpful to learn how to relax the muscles when the pain starts. By doing this, the circle of pain-spasm-pain can be interrupted. In the case of shortened muscles, relaxation alone is not enough. Stretching of the muscle is mandatory to regain length and function. Studies on physical therapy for pelvic floor pain syndrome have been sparse. A single blinded RCT with myofascial physical therapy and general body massage was carried out in patients with prostate or bladder pain. The global response rate to treatment with massage was significantly better in the prostate than in the bladder pain group (57% vs. 21%). In the prostate pain group, there was no difference between the two treatment arms. In the bladder pain group, myofascial treatment did significantly better than massage. Massage only improved complaints in the prostate pain group. The fact that gender distribution was different in each group is mentioned as a possible confounding factor [317]. Myofascial trigger point release Treatment of myofascial trigger points can be done by manual therapy, dry needling and wet needling. The evidence for all the different treatments is weak, with most studies showing no significant difference between these techniques, though most studies were small and heterogeneous with regards to the patients and methods. There is no evidence that manual techniques are more effective than no treatment [318]. Most studies of dry needling have compared with wet needling. Different systematic reviews have come to the conclusion that, although there is an effect of needling on pain, it is neither supported nor refuted that this effect is better than placebo [319]. Physiotherapy in PBPS Transvaginal manual therapy of the pelvic floor musculature (Thiele massage) in PBPS patients with high-tone dysfunction of the pelvic floor significantly improved several assessment scales [320]. The role of specific levator ani trigger point injections in women with chronic pelvic pain has been studied [321]. Each trigger point was identified by intravaginal palpation and injected with bupivacaine, lidocaine and triamcinolone. Seventy-two percent of women improved with the first trigger point injection, with 33% being completely pain-free. Efficacy and safety of pelvic floor myofascial physical therapy has been compared with global therapeutic massage in women with PBPS; global response assessment (GRA) rate was 59% and 26%, respectively. Pain, urgency and frequency ratings, and symptoms decreased in both groups during follow-up, and did not differ significantly between the groups. This suggests that myofascial physical therapy is beneficial in women with PBPS [322]. Primary Anal Pain Syndrome An RCT demonstrated that biofeedback treatment was superior to electrogalvanic stimulation and massage of the Levator muscle for treating chronic primary anal pain syndrome [126]. One hundred and fifty-seven patients who had at least weekly rectal pain were investigated, but only patients with tenderness on traction of the pelvic floor showed a significant treatment benefit. In patients with tenderness of the puborectalis muscle (Rome II: “Highly likely Levator Ani Syndrome”), 87% reported adequate relief after one month of biofeedback vs. 45% for electrogalvanic stimulation, and 22% for massage. These results were maintained at twelve months with adequate relief after nine sessions of biofeedback in 58% of the whole group (Rome II: “Highly likely” and “Possible Levator Ani Syndrome”), after galvanic stimulation in 27% and massage in 21% of patients. As previously described in dyssynergic defecation, the ability to expel a 50 mL water filled balloon and to relax pelvic floor muscles after biofeedback treatment were predictive of a favourable therapeutic outcome

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[126]. The pathophysiology of the chronic primary anal pain syndrome is therefore similar to that of dyssynergic defecation, and this favours the role of the pelvic floor muscles in the pathophysiology of both conditions. Other treatment modalities have been less successful. Treatment of sexual dysfunctions and chronic pelvic pain Couples often benefit from early referral for relationship and sexual counselling during their treatment course [323]. It needs to be remembered that sexual difficulties will arise as a result of pelvic pain syndromes as well as those disorders potentially being primary. Specific behavioural strategies for women who have urogenital complaints and female sexual dysfunction often include exploring alternatives to sexual intercourse (manual or oral pleasuring), different coital positions (female superior or side lying), and pacing, such as limiting the activity to less than that which causes pain. Planning for the time of intercourse is important, and scheduling a clinic visit after intercourse might be useful to identify specific sites and causes of post-coital flares. The corresponding evidence in men is lacking, but similar principles would apply. Other behavioural changes involve pre- and post-coital voiding, application of ice packs to the genital or suprapubic area [323, 324], and increased use of vaginal dilators, fingers or sex toys. Lubricants can also be used and women with signs of vulvovaginal atrophy may benefit from oestrogen cream [325]. Optimising the pelvic floor muscle is indicated when dysfunction is present and will relief the pain [326-328]. Other physical therapy interventions Electromagnetic therapy. A small, sham-controlled, double-blind study of four weeks showed a significant, sustained effect over a one-year period for CPPPS [329]. Microwave thermotherapy. In uncontrolled studies significant symptomatic improvement has been reported from heat therapy, for example, transrectal and transurethral thermotherapy [330, 331]. Extracorporeal shockwave therapy. A small sham-controlled double-blind study of four times weekly perineal extracorporeal shockwave therapy (n=30) in men with CPPPS showed significant improvement in pain, QoL, and voiding compared to the control group (n=30) over twelve weeks [332]. Two other randomised shamcontrolled studies, have been published more recently, one comparing ten treatment sessions over two weeks (n=40 vs. n=40) [333], another with four times weekly treatments (n=20 vs. n=20) [334]. Both concluded there was a significant effect in terms of total NIH-CPSI score and pain at twelve weeks. Unfortunately, no long term effects at 24 weeks could be shown in a published follow-up study of the second [335]. A recent Cochrane review of non-pharmacological interventions for chronic pelvic pain reported a reduction in symptoms following treatment compared with control and concluded that extracorporeal shockwave therapy may improve symptoms without an increase in adverse events [336]. Acupuncture. In a small three-arm randomised trial of CPPPS in men, electro-acupuncture was superior to sham treatment and advice and exercise alone [337]. Another more recent randomised study comparing acupuncture (n=50) vs. sham-controlled (n=50) once weekly treatment for six weeks showed significant long lasting improvement at 24 weeks in terms of response rate and overall symptom scores [338]. Another RCT showed a significant effect for a follow-up of 32 weeks [339]. Two systematic reviews and meta-analyses were published in 2016 analysing seven randomised-controlled studies on a total of 471 participants comparing acupuncture to sham control or oral medical treatment [340, 341]. Both came to the conclusion that acupuncture was effective and safe, significantly reducing total NIH-CPSI scores compared to sham or medical treatment, and should be considered as a treatment option. This is in line with the conclusion of a recent Cochrane systematic review [336] on non-pharmacological treatment options. However, the durability of this effect is not known. Posterior tibial nerve stimulation. See section 5.3.2, Neuromodulation. Transcutaneous electrical nerve stimulation. See section 5.3.2, Neuromodulation. 5.1.3 Psychological therapy Psychological interventions may be directed at pain itself or at adjustment to pain in terms of function and mood and reduced health-care use, with or without pain reduction. Ideally, treatment follows general principles and practice in the field of chronic pain [342, 343] but these have been neglected in pelvic pain. Two systematic reviews and meta-analyses of the few heterogeneous trials of psychologically based treatment for pelvic pain [344, 345] found benefits over a few months for pain, of around 50%, comparable to that from pharmacotherapy, but this was not sustained at follow-up. Exposure to pain-related fears in women with chronic pelvic pain proved superior to manual therapy in reducing those fears and overall pain disability, albeit assessed only by self-report [346]. More standard multi-component psychologically-based programmes are in the pilot stages [347]. One that combined mixed psychological therapies with acupuncture for endometriosisrelated pain, reported significant pain reduction at two year follow-up [348]. Indeed acupuncture is the only complementary treatment to have alleviated pain in this group [349]. Three more standard multicomponent (including psychological) treatments for pain [278, 316, 350] did not provide pain or symptom relief. Another

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RCT of multi-component treatment showed no effect on pain but benefits for distress [351], as did an RCT of mindfulness meditation for women with bladder pain [352]. The importance of multi-disciplinary treatment is emphasised by several reviews [43, 353, 354]. For less disabled and distressed patients, this can be delivered in part over the internet [355]. 5.1.4 Dietary treatment Scientific data are limited and dietary restriction alone does not produce significant symptomatic relief; however, consider the involvement of a dietician.

5.2

Pharmacological management

5.2.1 Drugs for chronic primary pelvic pain syndrome In this section the evidence available for specific CPPPSs is presented. Where there is no evidence the reader is directed to the section on analgesics below (Section 5.2.2) where more generic use is discussed. There is a large discrepancy in the treatment effects reported in case series and controlled trials that results from a large placebo effect or publication bias. As a result of the multifactorial origin of for example PPPS, one reason for treatment failure in some large randomised placebo-controlled trials may be the heterogeneity of the patient population. One strategy for improving treatment effects may be stratification of patient phenotypes. A prospective series of phenotypically directed treatment for PPPS has shown significant improvement of symptoms and QoL [356]. Monotherapeutic strategies for the treatment of PPPS may fail [357], therefore, most patients require multimodal treatment aimed at the main symptoms, and taking comorbidity into account. In the past ten years, results from RCTs have led to advances in standard and novel treatment options. 5.2.1.1 Mechanisms of action Mechanisms of action are discussed as appropriate under the drugs headings below. 5.2.1.2

Comparisons of agents used in pelvic pain syndromes

Primary Prostate Pain Syndrome (PPPS) Anti-inflammatory drugs For non-steroidal anti-inflammatory agents (NSAIDs), a trial with celecoxib reported that the pain sub-score, QoL sub-score, and total NIH-CPSI score were in favour of the treatment arm vs. placebo, but effects were limited to the duration of therapy [358]. In a meta-analysis, two studies of NSAIDs [269, 358] and one with prednisolone [359] were pooled. Anti-inflammatory drugs were 80% more likely to have a favourable response than placebo. In an updated network meta-analysis with more restrictive inclusion criteria regarding documented outcome measures but a wider spectrum of drugs (including glycosaminoglycans, phytotherapy and tanezumab), a significant effect on total NIH-CPSI scores and treatment response rates could be demonstrated. Overall, a moderate treatment effect has been shown for anti-inflammatory drugs, but larger studies are needed for confirmation, and long-term side-effects have to be taken into account. α-blockers Positive results from RCTs of α-blockers, i.e. terazosin [360, 361], alfuzosin [362], doxazosin [363, 364], tamsulosin [365, 366], and silodosin [367] have led to widespread use of α-antagonists in the treatment of PPPS in recent years. Whereas one systematic review and meta-analysis has not reported a relevant effect of α-blockers due to study heterogeneity [368], another network meta-analysis of α-blockers [367] has shown significant improvement in total symptoms, pain, voiding, and QoL scores. In addition, they had a higher rate of favourable response compared to placebo [relative risk (RR): 1.4, 95% CI: 1.1-1.8, p=0.013]. However, treatment responsiveness, i.e., clinically perceptive or significant improvement, may be lower than expected from the change in mean symptom scores. Overall, α-blockers seem to have moderate but significant beneficial effects. This probably is not the case for long-standing PPPS patients [369]. Future studies should show if longer duration of therapy or some sort of phenotypically directed (e.g., patients with PPPS and relevant voiding dysfunction) treatment strategies will improve treatment outcomes. Antibiotic therapy Empirical antibiotic therapy is widely used because some patients have improved with antimicrobial therapy. Patients responding to antibiotics should be maintained on medication for four to six weeks or even longer. Unfortunately, culture, leukocyte and antibody status of prostate-specific specimens do not predict antibiotic response in patients with PPS [370], and prostate biopsy culture findings do not differ from those of healthy controls [371]. The only randomised placebo-controlled trials of sufficient quality have been done for oral

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antibiotic treatment with ciprofloxacin (six weeks) [372], levofloxacin (six weeks) [373], and tetracycline hydrochloride (twelve weeks) [374]. The studies have been analysed in meta-analyses [367, 375]. Although direct meta-analysis has not shown significant differences in outcome measures, network meta-analysis has suggested significant effects in decreasing total symptom, pain, voiding, and QoL scores compared with placebo. Combination therapy of antibiotics with α-blockers has shown even better outcomes in network meta-analysis. Despite significant improvement in symptom scores, antibiotic therapy did not lead to statistically significant higher response rates [375]. In addition, the sample sizes of the studies were relatively small and treatment effects only modest and most of the time below clinical significance. It may be speculated that patients profiting from treatment have had some unrecognised uropathogens. If antibiotics are used, other therapeutic options should be offered after one unsuccessful course of a quinolone or tetracycline antibiotic over six weeks. 5-α-reductase inhibitors Although a few small pilot studies with 5-α-reductase inhibitors supported the view that finasteride may improve voiding and pain, the first RCT published in a peer-reviewed journal did not support this, although the study lacked power [376]. In another RCT, finasteride provided better amelioration of symptoms compared to saw palmetto over a one-year period, but lacked a placebo-control arm [377]. A six-month placebo-controlled study showed a non-significant tendency towards better outcome in favour of finasteride, possibly because of a lack of statistical power [366]. The NIH-CPSI scores decreased significantly in a subgroup of men enrolled in a prostate cancer risk reduction study treated with dutasteride compared to placebo [367]. Patients (n=427, age 50 to 75, with elevated prostate-specific antigen [PSA]) were included if they had significant “prostatitis-like” symptoms at baseline. Based on the evidence, 5-α-reductase inhibitors cannot be recommended for use in PPPS in general, but symptom scores may be reduced in a restricted group of older men with an elevated PSA [367]. Phytotherapy Phytotherapy applies scientific research to the practice of herbal medicine. An adequately powered placebocontrolled RCT of a pollen extract (Cernilton) showed clinically significant symptom improvement over a twelveweek period in inflammatory PPPS patients (NIH Cat. IIIA) [378]. The effect was mainly based on a significant effect on pain. Another pollen extract (DEPROX 500) has been shown to significantly improve total symptoms, pain and QoL compared to ibuprofen [379]. A systematic review and meta-analysis of pollen extract for the treatment of PPPS showed significant improvement in overall QoL [380]. Quercetin, a polyphenolic bioflavonoid with documented antioxidant and anti-inflammatory properties, improved NIH-CPSI scores significantly in a small RCT [381]. In contrast, treatment with saw palmetto, most commonly used for “benign prostatic hyperplasia”, did not improve symptoms over a one-year period [377]. In a SR and meta-analysis, patients treated with phytotherapy were found to have significantly lower pain scores than those treated with placebo [367]. In addition, overall response rate in network meta-analysis was in favour of phytotherapy (RR: 1.6; 95% CI: 1.1-1.6). Pregabalin is an anti-epileptic drug that has been approved for use in neuropathic pain. In an adequately powered randomised placebo-controlled study, which was the only report included in a published Cochrane review [382], a six-week course of pregabalin (n=218) compared to placebo (n=106) did not result in a significant reduction of NIH-CPSI total score [383]. Pentosane polysulphate is a semi-synthetic drug manufactured from beech-wood hemicellulose. One study using oral high-dose (3 x 300 mg/day) demonstrated a significant improvement in clinical global assessment and QoL over placebo in men with PPPS, suggesting a possible common aetiology [384]. Muscle relaxants (diazepam, baclofen) are claimed to be helpful in sphincter dysfunction or pelvic floor/ perineal muscle spasm, but there have been few prospective clinical trials to support these claims. In one RCT, a triple combination of a muscle relaxant (thiocolchicoside), an anti-inflammatory drug (ibuprofen) and an α-blocker (doxazosin) was effective in treatment-naïve patients, but not superior to an α-blocker alone [364]. Botulinum toxin type A (BTX-A) showed some effect in the global response assessment and the NIHCPSI pain subdomain score in a small randomised placebo-controlled study of perineal skeletal muscle injection (100 U). However, patient numbers were low (thirteen in the BTX-A group and sixteen in the placebo group), and follow-up was too short to draw definitive conclusions. Side-effects are unclear [385]. In another randomised-controlled study of intraprostatic injection of BTX-A (100 or 200 U depending on prostate volume) vs. placebo (n=30 in both groups) a significant improvement of total NIH-CPSI and subdomain scores could be shown at six months [386]. However, no real placebo effect could be demonstrated, which suggests unblinding. No definitive conclusion can be drawn.

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Zafirlukast, a leukotriene antagonist, and prednisone in two low-power placebo-controlled studies failed to show a benefit [359, 387]. More recently, a placebo-controlled phase IIa study of tanezumab, a humanised monoclonal antibody that specifically inhibits the pain mediating neurotrophin, nerve growth factor, failed to demonstrate significant effect [388] and should only be used in clinical trials. Allopurinol There is insufficient evidence for the use of allopurinol in PPPS [389, 390]. Primary Bladder Pain Syndrome (PBPS) Treatments of significant value for BPS Anti-histamines Mast cells may play a role in PBPS. Histamine is one of the substances released by mast cells. Histamine receptor antagonists have been used to block the H1 [391] and H2 [392] receptor subtypes, with variable results. A prospective placebo-controlled RCT of hydroxyzine or oral pentosane polysulphate did not show a significant effect [393]. Amitriptyline Amitriptyline is a tricyclic antidepressant. Several reports have indicated improvement of PBPS symptoms after oral amitriptyline [394]. Amitriptyline has been shown to be beneficial when compared with placebo plus behavioural modification [395]. Drowsiness is a limiting factor with amitriptyline, nortriptyline is sometimes considered instead. Pentosane polysulphate Is a semi-synthetic drug manufactured from beech-wood hemicellulose. Subjective improvement of pain, urgency, frequency, but not nocturia, has been reported [396, 397]. Pentosane polysulphate had a more favourable effect in PBPS type 3 C than in non-lesion disease [398]. Response was not dose dependent but related more to treatment duration. At 32 weeks, about half the patients responded. Combination therapy showed a response rate of 40% compared to 13% with placebo. For patients with an initial minor response to pentosane polysulphate, additional subcutaneous heparin was helpful [399, 400]. Immunosuppressants Azathioprine treatment has resulted in disappearance of pain and urinary frequency [401]. Initial evaluation of cyclosporin A (CyA) [402] and methotrexate [403] showed good analgesic effect but limited efficacy for urgency and frequency. Corticosteroids are not recommended in the management of patients with PBPS because of a lack of evidence. Intravesical Treatments Intravesical drugs are administered due to poor oral bio-availability establishing high drug concentrations within the bladder, with few systemic side-effects. Disadvantages include the need for intermittent catheterisation which can be painful in PBPS patients, cost and risk of infection [404]. • Local anaesthetics There are sporadic reports of successful treatment of PBPS with intravesical lidocaine [405, 406]. Alkalisation of lidocaine improves its pharmacokinetics [407]. Combination of heparin, lidocaine and sodium bicarbonate gave immediate symptom relief in 94% of patients and sustained relief after two weeks in 80% [408]. Intravesical instillation of alkalised lidocaine or placebo for five consecutive days resulted in significantly sustained symptom relief for up to one month [409]. • Hyaluronic acid and chondroitin sulphate These are described to repair defects in the GAG layer. Despite the fact that intravesical GAG replenishment has been in use for about twenty years for PBPS/IC, most of the studies are uncontrolled and with a small number of patients. Based on the studies available there are differences by virtue of substance classes, whether they are natural GAG layer components, dosage formulations, or concentrations. A recent RCT seems to reinforce the case for GAG layer replenishment, however it lacks a placebo arm [410]. A meta-analysis confirms usefulness of GAG layer replenishment. However most retrieved studies are non-randomised and with scarce numbers [411].

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• Intravesical heparin Primary bladder pain syndrome patients were treated with heparin for three months, and over half had control of symptoms, with continued improvement after one year of therapy [412]. Kuo reported another trial of intravesical heparin for three months in women with frequency-urgency syndrome and a positive potassium test. Symptomatic improvement was reported in 80% of PBPS patients [413]. Intravesical heparin plus peripheral neuromodulation in patients with refractory PBPS was studied and it was shown that voiding frequency, pain score and maximum cystometric capacity were significantly better after two and twelve months [414]. • Hyperbaric oxygen This has a moderate effect on a small subgroup of PBPS patients. Disadvantages include high cost, limited availability of treatment sites, and time-consuming treatment [399]. Treatments of limited value for BPS Cimetidine There are limited data to suggest that cimetidine improves symptoms of PBPS in the short-term. Compared with placebo for three months, cimetidine significantly improved symptom scores, pain and nocturia, although the bladder mucosa showed no histological changes in either group [415]. Prostaglandins Misoprostol is a prostaglandin that regulates various immunological cascades. After three months of treatment with misoprostol, 14 out of 25 patients had significantly improved, with twelve showing a sustained response after a further six months [416]. The incidence of adverse drug effects was 64%. L-Arginine Oral treatment with the nitric oxide (NO) synthase substrate L-arginine decreases PBPS-related symptoms [417-419]. Nitric oxide is elevated in patients with PBPS [420]. However, others have not demonstrated symptomatic relief or changes in NO production after treatment [421, 422]. Oxybutynin is an anti-cholinergic drug used in overactive detrusor dysfunction. Intravesical oxybutynin combined with bladder training improves functional bladder capacity, volume at first sensation, and cystometric bladder capacity [423]. However, an effect on pain has not been reported. Duloxetine (a serotonin-noradrenaline re-uptake inhibitor antidepressant with a licence for the management of neuropathic pain) did not significantly improve symptoms of PBPS [424]. Administration was safe, but tolerability was poor due to nausea. Based on these preliminary data, duloxetine cannot be recommended for treatment of PBPS. Primary Scrotal Pain Syndrome (PSPS) Treatment of primary scrotal pain syndrome is based on the principles of treating chronic pain syndromes, as described throughout these guidelines. In men with pain post inguinal hernia repair, there is limited evidence from case series showing that neurectomy of the damaged nerves can lead to symptomatic benefit [192, 425]. For scrotal pain post vasectomy, affected men may find that reversal of vasectomy can cure symptoms especially in those in whom patency is achieved [426]. In a prospective RCT, pulsed radio-frequency to the ilioinguinal and genitofemoral nerves is associated with high rates of symptomatic improvement (80%) but follow up was limited to 3 months [427]. The evidence for epididymectomy is poor but if considered, is less likely to provide benefit if the epididymis has a normal sonographic appearance [428]. Chronic gynaecological pain It is difficult to compare the wide variation of drugs from an efficacy and safety perspective as they have such diverse uses/indications. In those gynaecological patients where chronic pelvic pain is unrelated to any of the well-defined conditions, it is often difficult to determine a therapeutic pathway other than a multi-disciplinary chronic abdomino-pelvic pain management plan. A Cochrane review suggests there may be some evidence (moderate) supporting the use of progestogens [344]. Though efficacious, physicians need to be knowledgeable of progestogenic side

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effects (e.g., weight gain, bloatedness - the most common adverse effects) which can stop some patients from accepting such medication. Gonadotrophins, such as goserelin, are also thought to help such pain. However, when compared with progestogens, their efficacy remains limited. The quality of evidence is generally low and is drawn from single studies [344]. Gonadotropin-releasing hormone (GnRH) on the other hand binds to specific receptors on pituitary gonadotrophs, leading to desensitisation and consequently to suppressed gonadotropin secretion. By contrast, GnRH antagonists compete with GnRH for receptors thus gonadotrophin secretion, which may be beneficial in certain clinical applications, such as reducing the size of fibroids, endometrial bleeding and endometriosis [429]. Pelvic Floor, Abdominal and Chronic Anal Pain Botulinum toxin type A (pelvic floor) Botulinum toxin type A has been injected into trigger points. It is more expensive than lidocaine and has not been proven to be more effective [430]. Reviews do not support the injection of BTX-A into trigger points [431]. Pelvic floor muscle over-activity plays a role in CPPS. Botulinum toxin type A, as a muscle relaxant, can be used to reduce the resting pressure in the pelvic floor muscles. In women with high resting pressure in the pelvic floor muscles, it has been found that BTX-A lowers this pressure significantly. The magnitude of reduction was significantly higher than that in the placebo group. On the VAS pain score, no intergroup differences were found in this relatively small randomised study [432]. Botulinum toxin type A can also be injected at the sphincter level to improve urination or defecation. Relaxation of the urethral sphincter alleviates bladder problems and secondarily the spasm. In a cohort study of thirteen patients with CPPPS, BTX-A was injected into the external urethral sphincter. Subjectively, eleven patients reported a substantial change in pain symptoms, from a score of 7.2 to 1.6 on a VAS [433]. Botulinum toxin type A (chronic primary anal pain syndrome) In CPPPS associated with spasm of the levator ani muscles, treatment of the puborectalis and pubococcygeus muscle by BTX-A appears to be promising in some women, as shown in a pilot study (n=12). The inclusion criteria were dependent only on vaginal manometry with over-activity of the pelvic floor muscles, defined as a vaginal resting pressure > 40 cm H2O. Although dyspareunia and dysmenorrhoea improved, non-menstrual pelvic pain scores were not significantly altered [434]. In the following double-blinded, randomised, placebocontrolled trial, the same group defined pelvic floor myalgia according to the two criteria of tenderness on contraction and raised muscle tension (> 40 cm H2O) and included 60 women. In this larger study, nonmenstrual pelvic pain was significantly improved compared to those treated with placebo (VAS score 51 vs. 22; p=0.009). It was concluded therefore that BTX-A is effective at reducing pelvic floor-muscle associated pain with acceptable adverse effects such as occasional urinary and faecal stress incontinence [420]. However, recently, a small RCT failed to show any benefit of BTX-A [435]. Intermittent chronic primary anal pain syndrome Due to the short duration of the episodes, medical treatment and prevention is often not feasible. Inhaled β-2 adrenergic agonist salbutamol was effective in an RCT in patients with frequent symptoms and shortened pain duration [436]. Other treatment options are topic diltiazem and BTX-A [437]. However, there is still some controversy regarding the duration of pain of intermittent chronic and chronic primary anal pain syndrome. Randomised controlled trials often use different definitions, extending the pain duration (with a shift to chronic pain) in order to include more patients and to better evaluate the study-drug action. Abdominal pain associated with Irritable Bowel Syndrome Linaclotide, a minimally absorbed peptide guanylate cyclase-C agonist at a dose of 290 μg once daily significantly improved abdominal pain (48.9% vs. 34.5% placebo-treated) and bowel symptoms associated with IBS with constipation over 26 weeks of treatment [438]. Diarrhoea was the most common adverse event in patients treated with linaclotide (4.5%). Although it is known to overlap with IBS pelvic pain, effect on the latter was not assessed in this study. Delta-9-tetrahydrocannabinol (THC) shows only equivocal evidence of analgesic effects in chronic primary abdominal pain. In a recently published phase II trial, no difference was found between THC tablet and a placebo tablet in reducing pain outcome in patients with chronic abdominal pain [439]. 5.2.2 Analgesics If the use of simple analgesics fails to provide adequate benefit, then consider using neuropathic agents, and if there is no improvement, consider involving a specialist pain management centre with an interest in pelvic pain. Chronic pelvic pain is well defined and involves multiple mechanisms as described in previous sections.

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The management requires a holistic approach with biological, psychological and social components. Few studies have specifically looked at medications used in CPPPS [440], therefore, a wider look at the literature has been undertaken and further specific research is required. The agents concerned are divided for ease of description. Combinations often provide a greater benefit than individual agents. They may also allow lower individual dosages and thus minimise side-effects. The aim of using these drugs is to allow patients to improve their QoL. This is best measured by assessing their function as well as pain severity. If the use of these agents does not allow this, then they should be withdrawn. Unfortunately, the failure of one agent does not exclude potential benefit of an alternative. If the benefit is limited by side-effects, then the lowest effective dose should be found (by dose titration). Sometimes, patients will prefer a higher level of pain and have fewer side-effects. 5.2.2.1 Mechanisms of action Mechanisms of action are discussed as appropriate under the drug headings below. 5.2.2.2

Comparisons within and between groups in terms of efficacy and safety

Paracetamol (acetaminophen) Paracetamol is a well-tolerated analgesic in a class of its own. This is an antipyretic analgesic with a central mechanism of action [441]. It is often available over the counter without prescription. A review questions its routine use as a first-line analgesic based on inadequate evidence of efficacy in many pain conditions including dysmenorrhoea [442]. It will not be effective for all patients and individual responses should be reviewed when deciding on longer term use. Non-steroidal anti-inflammatory agents (NSAIDs) These agents are anti-inflammatory, antipyretic analgesics that act by inhibiting the enzyme cyclooxygenase (COX). They have a peripheral effect, hence their use in conditions involving peripheral or inflammatory mechanisms. They are commonly used for pelvic pain; many are available over the counter and are usually well-tolerated. There is insufficient evidence to suggest one NSAID over another for pelvic pain. Guidelines for use of NSAIDs and COX-2 selective agents have been developed. They have more side-effects than paracetamol, including indigestion, headaches and drowsiness. The evidence for their benefit in chronic pelvic pain is weak or non-existent and is often limited by side-effects. For pelvic pain in which inflammatory processes are considered important, such as dysmenorrhoea [443], NSAIDs are more effective than placebo and paracetamol, but with a higher incidence of side-effects. For pelvic pain in which central mechanisms may be incriminated, such as endometriosis [444], then the evidence is lacking for NSAIDs despite their common use. At a practical level, if NSAIDs are considered for use, they should be tried (having regard for the cautions and contraindications) and the patient reviewed for improvement in function as well as analgesia. If this is not achieved, or side-effects are limiting, then they should be withdrawn. Neuromodulators These are agents that are not simple analgesics but used to modulate neuropathic or centrally mediated pain. There are several classes commonly used with recognised benefits in pain medicine. They are taken on a regular basis and all have side-effects that may limit their use. In the UK, the National Institute for Health and Clinical Excellence (NICE) has reviewed the pharmacological management of neuropathic pain [445]. Not all the agents are licensed for use in pain management but there is a history and evidence to demonstrate their benefit. The evidence for treatment of CPPPS is lacking but is present for other painful conditions. For this chapter, most of the evidence is from non-pelvic pain sources. The general method for using these agents is by titrating the dose against benefit and side-effects. The aim is for patients to have an improvement in their QoL, which is often best assessed by alterations in their function. It is common to use these agents in combination but studies comparing different agents against each other, or in combination, are lacking. Some of these agents are also used for specific conditions. Early identification of neuropathic pain with a simple questionnaire could facilitate targeted therapy with neuromodulators [59]. Antidepressants Tricyclic antidepressants The tricyclic antidepressants (TCAs) have multiple mechanisms of action including, blockade of acetylcholine receptors, inhibition of serotonin and noradrenaline re-uptake, and blockade of histamine H1 receptors. They also have anxiolytic affects [446] and are frequently limited by their side-effects. Tricyclic antidepressants have a long history of use in pain medicine and have been subjected to a Cochrane review [447], suggesting that

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they are effective for neuropathic pain. Amitriptyline is the most commonly used at doses from 10 to 75 mg/day (sometimes rising to 150 mg/day). This is titrated against benefit or side-effects and can be taken at night [445]. Nortriptyline and imipramine are used as alternatives. Other Antidepressants Duloxetine is a serotonin-noradrenaline re-uptake inhibitor (SNRI) antidepressant licensed for use in depression, urinary stress incontinence and neuropathic pain. There is moderately strong evidence of benefit in diabetic neuropathy and fibromyalgia at a dose of 60 mg/day [448]. Side-effects are common and may result in its discontinuation. Selective serotonin re-uptake inhibitors are antidepressants with fewer side-effects. They are effective for depression, but there have been insufficient studies to demonstrate their benefit in pelvic or neuropathic pain [447-449]. Anticonvulsants Anticonvulsants are commonly used in the management of neuropathic pain. There are general studies and some looking more particularly at pelvic pain. Individual agents have been systematically reviewed. Their use is suggested in the NICE Neuropathic Pain Guidelines [445]. There is a growing awareness and evidence of the risk for dependence and misuse of gabapentinoids [450]. A formal assessment of efficacy against benefit and side-effects (both pain and QoL) is required with the patient in order to determine the lowest effective dose and if longer-term treatment is to be used. Carbamazepine has a long history of use in neuropathic pain. Evidence exists for its benefit [451]. Trials trend to be of short duration, showing only moderate benefit. There are side-effects; some of which may be serious. It is no longer a first choice agent. Other anticonvulsant agents are available with fewer serious side-effects. Gabapentin is commonly used for neuropathic pain and has been systematically reviewed [452]. It provides good quality relief with number needed to treat (NNT) of approximately six. Side-effects are common, notably drowsiness, dizziness and peripheral oedema. For higher dose levels, reference should be made to local formularies, and many clinicians do not routinely exceed 2.4 g/day in divided doses (most commonly three times daily). One study of women with CPPPS has suggested that gabapentin alone or in combination with amitriptyline provides better analgesia than amitriptyline alone [453]. A more recent pilot study suggests that gabapentin is beneficial and tolerable; a larger study is required to provide a definitive result [454]. Pregabalin is a commonly used neuromodulator with good evidence of efficacy in some neuropathic conditions but the NNT varies depending on the condition [455]. The dose for benefit is in the range of 300 to 600 mg/ day. The same SR found that doses less than 150 mg/day are unlikely to provide benefit. A review for CPPS (prostate) only found a single reviewable study that does not show overall symptom improvement but suggests individual symptoms may improve (e.g., pain, QoL) and side-effects were common demonstrating the need for further robust studies [382]. As with gabapentin, side-effects are common and may not be tolerated by patients. A formal assessment of efficacy against side-effects is required with the patient in order to determine longer-term treatment. Other anticonvulsants are available but not commonly used for managing pain. Other agents can be used in the management of neuropathic pain but they are best administered only by specialists in the management of pain and familiar with their use. They tend to be considered after the standard options have been exhausted. As with all good pain management, they are used as part of a comprehensive multidimensional management plan. Opioids Over recent years opioids have been used extensively for managing chronic non-cancer pain. There is increasing evidence that their role is limited in this population but may be beneficial for a small number of patients at a low dose in a managed setting [456]. There is clear evidence of harm and significant professional, public and political interest. Their use is beneficial for both acute pain and for cancer pain management particularly towards the end of life. Often patients will stop taking oral opioids due to side effects or insufficient analgesic effect [457]. There is clear evidence of harm including effects on the endocrine and immune systems as well as a growing understanding of opioid-induced hyperalgesia [458]. There is limited guidance on the best method for tapering the dose of opioids with the aim of stopping or finding the lowest effective dose [459].

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Opioids should only be used in conjunction with a management plan with consultation between clinicians experienced in their use. It is suggested that a pain management unit should be involved along with the patient and their primary care physician. Ensure there are arrangements for formal monitoring, follow-up and review. If opioids are used and the pain remains, then they are not working and should be stopped even if there is no alternative [458]. The risk of harm increases substantially at doses above 120 mg/day morphine equivalence [458] and guidance suggests regular (at least annual) review for patients with over 50 mg/day morphine equivalence and pain specialist involvement above 90 mg/day morphine equivalence [460]. There are well-established guidelines for the use of opioids in pain management as well as considering the potential risks [458, 460]. Opioid reduction and optimisation should be undertaken where opioids are not providing clear measurable benefit. There is also information available online for patients [458]. Opioids Aware is a web-based resource for patients and healthcare professionals, jointly produced by the Faculty of Pain Medicine of Royal College of Anaesthetists and Public Health England, to support prescribing of opioid medicines for pain. https://fpm.ac.uk/opioids-aware. Cannabinoids There has been increasing interest and changes in national regulations regarding the use of cannabinoids for medicinal use. Regarding pain the evidence base for the use of cannabinoids is weak [461-463] and further well conducted clinical trials are necessary. This is an area where further guidance and research is likely in the coming years.

5.3

Further management

5.3.1 Nerve blocks Nerve blocks for pain management are usually carried out by specialists in pain medicine as part of a broader management plan [464]. They may have a diagnostic or therapeutic role. Textbooks have been written on the subject and practitioners using them should be trained in appropriate patient selection, indications, risks and benefits. Many such interventions also require understanding and expertise in using imaging techniques to perform the blocks accurately. Diagnostic blocks can be difficult to interpret due to the complex mechanisms underlying the painful condition or syndrome. Sustained but limited benefit may lead to more permanent procedures (e.g., radiofrequency procedures). There is a weak evidence base for these interventions for chronic non-malignant pain [465]. Pudendal Neuralgia The role of injections may be divided into two. First, an injection of local anaesthetic and steroid at the sight of nerve injury may produce a therapeutic action. The possible reasons for this are related to the fact that steroids may reduce any inflammation and swelling at the site of nerve irritation, but also because steroids may block sodium channels and reduce irritable firing from the nerve [466]. However, a recent paper by Labat et al. challenges this [467]. The second possible benefit is diagnostic. It has already been indicated that when the pudendal nerve is injured there are several sites where this may occur. Differential block of the pudendal nerve helps to provide information in relation to the site where the nerve may be trapped [260, 468-475]. Infiltration at the ischial spine requires the use of a nerve stimulator/locator. Both motor (anal contraction) and sensory endpoints may be noted. The anatomical endpoint may be localised by fluoroscopy, CT guidance, or the use of US, the latter avoids any radiation, whereas CT guidance involves a significant amount of radiation. Currently, fluoroscopy is probably the imaging technique most frequently used because it is readily available to most anaesthetists that perform the block. Currently, infiltration of the pudendal nerve within Alcock’s canal is primarily undertaken with the use of CT. As well as injecting around the pudendal nerve, specific blocks of other nerves arising from the pelvis may be performed. Pulsed radio frequency stimulation has also been suggested as a treatment [476]. Pulsed radio frequency lesioning for pudendal neuralgia is being developed with a paper demonstrating potential benefit. Follow-up is short term and further research is required to better elucidate its place in management [477]. 5.3.2 Neuromodulation The role of neuromodulation in the management of pelvic pain should only be considered by specialists in pelvic pain management. These techniques are used as part of a broader management plan and require regular follow-up. The research base is developing and the techniques broadening (e.g., spinal cord stimulation [SCS], sacral root stimulation, dorsal root ganglion stimulation or peripheral nerve stimulation). These are expensive interventional techniques for patients refractory to other therapies. Neuromodulation is still finding its role in

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pelvic pain management. There has been growing evidence but more detailed, high quality research is required [478]. Its role in overactive bladder and faecal incontinence is more robust but is limited for pain. Two recent systematic reviews have evaluated neuromodulation techniques for CPPS [479, 480]. Both studies concluded that neuromodulation may be effective in reducing pain and improving QoL in patients with CPPS; however, studies were of a low quality and long-term results were needed. Transcutaneous Electrical Nerve Stimulation (TENS) Transcutaneous electrical nerve stimulation is a non-invasive technique used in many pain conditions. A SR identified twelve studies of TENS in chronic pelvic pain conditions including four RCTs [479]. All RCTs demonstrated a significant reduction in pain following twelve weeks of treatment for pain conditions including dysmenorrhoea and CPPPS. Pain was also found to improve following TENS for provoked vestibular pain. There was conflicting data with regard to improvement of QoL following TENS; where validated questionnaires were used, no significant improvement was found, whereas in trialist-defined studies, an improvement was seen in TENS for dysmenorrhea and CPPPS. The beneficial effects of a course of TENS may be sustained; one study demonstrating a persistent benefit at 43 months in 73% of men with CPPPS and another demonstrating a prolonged significant improvement in women with provoked vestibular pain at ten months post-treatment. Where reported there were no adverse events recorded. Transcutaneous electrical nerve stimulation could offer an effective non-invasive treatment option for patients with CPPPS. Percutaneous Tibial Nerve Stimulation (PTNS) Percutaneous tibial nerve stimulation is a minimally invasive technique that can be use in an outpatient setting. Two SRs have shown that PTNS is effective in reducing pain in patients with CPPPS [479, 480]. Three RCTs identified showed a significant improvement in pain scores and QoL as measured by validated questionnaires. Where recorded, adverse events were rare and minor including temporary slight pain at application site and haematoma. Sacral Nerve Stimulation (SNS) Sacral nerve stimulation is an invasive technique requiring sedation or general anaesthesia for implantation of a device following trial stimulation. A SR review identified ten studies of SNS in CPPPS, either retrospective case series or prospective cohort studies and no RCTs. Where reported, a mean of 69% of participants progressed to implantation of device following test stimulation (range 52-91%). All studies reported an improvement in pain, statistically significant in five studies. Quality of Life was measured in three studies and a significant improvement demonstrated in two of three studies. There was a large variation in adverse events reported ranging from 0-50%. Complications not requiring surgical intervention included pain, failure of device, wound infection and seroma. Re-operation rate ranged between 11-50% for complications including lead migration, systemic infection, intrathecal implantation, loss of efficacy and erosion. In clinical practice, a patient should be appropriately counselled regarding the need for a period of trial stimulation and whilst there may be an improvement in symptoms, this should be weighed against a notable complication rate. Other neuromodulation techniques A variety of other techniques of neuromodulation for patients with CPPPS were identified by a recent systematic review [479]. These techniques include intravaginal electrical stimulation for women with CPPPS, pudendal nerve stimulation for CPPPS, spinal cord stimulation for pudendal neuralgia, transcutaneous interferential electrical stimulation for IBS, electrical acupuncture for dysmenorrhoea and electrical stimulation/ biofeedback and electromagnetic stimulation for men with CPPPS. Whilst an improvement in pain has been reported in these studies, it is noted that they are largely of low quality and further work is needed in this area to enable robust clinical recommendations to be made. 5.3.3

Surgery

Primary Bladder Pain Syndrome (PBPS) Bladder distension Although bladder hydrodistension is a common treatment for PBPS, the scientific justification is scarce. It can be part of the diagnostic evaluation, but has limited therapeutic role. Hydrodistension and Botulinum toxin type A Botulinum toxin type A may have an anti-nociceptive effect on bladder afferent pathways, producing symptomatic and urodynamic improvements [481]. Treatment with hydrodistension and hydrodistension plus intravesical BTX-A has been compared [482]. There was symptomatic improvement in all patients. However,

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in the hydrodistension-only group, 70% returned to their previous symptoms after one month, while in the BTX-A-treated patients, VAS score and functional and cystometric bladder capacity improved at three months. Botulinum toxin type A trigonal-only injection seems effective and long-lasting as 87% of patients reported improvement after three months follow-up [483]. Over 50% reported continued benefit nine months after the first treatment. When re-treatment was needed, similar results were obtained. The authors concluded that this treatment is safe, effective and can be repeated. Adverse effects of BTX-A administration for IC/PBPS were significantly less than for overactive bladder syndrome, namely in increased post-void residual volumes and decreased voiding efficiency [484]. Recent RCTs have confirmed benefits and long efficacy of BTX-A administration [485-489]. The American Urological Association (AUA) guidelines panel has upgraded BTX-A treatment from fifth to a fourth line treatment. There is conflicting data on results, hindering issuance of a clear guideline for the use of botox in PBPS phenotypes [490]. Transurethral resection (TUR), coagulation and laser Endourological destruction of bladder tissue aims to eliminate urothelial Hunner lesions. Since the 1970s, resection and fulguration have been reported to achieve symptom relief, often for more than three years [491, 492]. Prolonged amelioration of pain and urgency has been described for transurethral laser ablation as well [493]. Open Surgery for PBPS Primary bladder pain syndrome is benign and does not shorten life, thus operative procedures rank last in the therapeutic algorithm. There is no evidence that it relieves pain. Surgery for PBPS is only appropriate as a last resort for patients with refractory disease. Major surgery should be preceded by thorough preoperative evaluation, with an emphasis on determining the relevant disease location and subtype. If surgery is considered, the panel’s advice is to refer the patient to a specialist centre experienced in managing CPPPS with a multi-disciplinary team approach. Four major techniques are common: 1. Urinary diversion without cystectomy is performed to minimise the duration and complexity of surgery, but complications related to the retained bladder commonly occur. Reports that un-resected PBPS bladders cease to induce symptoms after loss of contact with urine are scarce [104, 494]. 2.

Supratrigonal cystectomy with bladder augmentation represents the most favoured continencepreserving surgical technique particularly in younger patients [495]. Various intestinal segments have been used [496-498]. After orthotopic bladder augmentation, bladder emptying may be incomplete so intermittent self-catheterisation may be required. A study on female sexuality after cystectomy and orthotopic ileal neobladder showed pain relief in all patients and improvement in sexual function items in women who remained sexually active [499]. Pregnancies with subsequent lower-segment Caesarean section have been reported after ileocystoplasty [500].

3.

Subtrigonal or simple cystectomy refers to removal of the entire bladder at the level of the bladder neck. This approach has the benefit of removing the trigone as a possible disease site, but at the cost of requiring ureteric re-implantation. Trigonal disease is reported in 50% of patients and surgical failure has been blamed on the trigone being left in place [501], especially in patients with non-lesion type disease [502, 503]. However, in a previous study all patients were rendered symptom-free by supratrigonal resection compared to 82% of those undergoing subtrigonal cystectomy. Voiding dysfunction is most likely to occur following trigonal resection and patients considering augmentation and especially substitution procedures must be capable of accepting, performing and tolerating self-catheterisation [504].

4.

Cystectomy with formation of an ileal conduit is considered for patients with PBPS who develop recurrent pain in the augmented bladder, continent pouch after enterocystoplasty or continent urinary diversion. Re-tubularisation of a previously used bowel segment to form a urinary conduit has been recommended [505].

Primary Prostate Pain Syndrome There is no evidence for surgical management, including transurethral incision of the bladder neck, radical transurethral resection of the prostate or, in particular, radical prostatectomy in the management of chronic pain in patients with PPPS. Recently, a large Chinese randomised-controlled trial of circumcision combined with a triple oral therapy (ciprofloxacin, ibuprofen, tamsulosin) vs. oral therapy alone has been published for patients with PPPS (total n=774) [506]. It is hypothesised that there may be some immunological interaction via pathogenic antigen presenting cells in the foreskin with CD4+ T cells causing auto-immunity to the

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prostate gland. They reported an improvement in total NIH-CPSI score and subdomain scores at twelve weeks. However, despite a large cohort, the study results are questionable because of the weak theoretical background, and a potential large placebo effect lacking a sham control. In addition, no long-term effectiveness has been reported. Before having an impact on recommendations, the results of this study have to be independently confirmed and the treatment effect must persist. Primary Testicular Pain Syndrome Microsurgical denervation of the spermatic cord can be offered to patients with testicular pain. In a long-term follow-up study, patients who had a positive result on blocking the spermatic cord were found to have a good result following denervation [507, 508]. Chronic Primary Anal and Abdominal Pain Syndrome Chronic primary anal pain syndrome after stapled procedures, such as hemorrhoidopexy (PPH) or stapled transanal rectal resection (STARR) may respond to excision of the scarred staple line as shown in 21 consecutive patients with an overall improvement of pain in 85.7% of patients undergoing scar excision surgery [509]. An early scar excision before three to six months after pain onset was associated with better pain relief. Adhesiolysis is still in discussion in the pain management after laparotomy/laparoscopy for different surgical indications in the pelvis and entire abdomen. A recent study has shown, that adhesiolysis is associated with an increased risk of operative complications, and additional operations and increased health care costs as compared to laparoscopy alone [510]. Primary Urethral Pain Syndrome There is no specific treatment that can be advised. Management should be multi-disciplinary and multi-modal [511]. Laser therapy of the trigonal region may be a specific treatment. One trial comparing two forms of laser reported good results, but did not compare with sham treatment [512]. The majority of publications on treatment of primary urethral pain syndrome have come from psychologists [168]. Presumed intra-abdominal adhesions In gynaeocological patients with CPPPS and presumed adhesions, there is no consensus as to whether adhesiolysis should be performed to improve pain [513]. Extensive surgery for endometriosis is challenging and is still considered to be controversial, as there is at least one RCT showing no benefit in pain relief after the removal of early extensive endometriosis compared to sham surgery [272, 514]. In patients with adenomyosis, the only curative surgery is hysterectomy but patients can benefit from hormonal therapy and analgesics (see Section 5.2.2). Pudendal neuralgia and surgery Decompression of an entrapped or injured nerve is a routine approach and probably should apply to the pudendal nerve as it applies to all other nerves. There are several approaches and the approach of choice probably depends upon the nature of the pathology. The most traditional approach is transgluteal; however, a transperineal approach may be an alternative, particularly if the nerve damage is thought to be related to previous pelvic surgery [198, 260, 515-518]. Currently, there has been only one prospective randomised study (transgluteal approach) [517]. This study suggests that, if the patient has had the pain for less than six years, 66% of patients will see some improvement with surgery (compared to 40% if the pain has been present for more than six years). Surgery is not the answer for all patients. On talking to patients that have undergone surgery, providing the diagnosis was clear-cut, most patients were grateful to have undergone surgery but many still have symptoms that need management. Chronic Pelvic Pain and Prolapse/Incontinence Mesh Removing an existing mesh is a complex procedure [519]. Each patient is approached on an individual basis depending on the type of mesh and extent of complications [520]. The complexity of surgery often involves removal of dense scar tissue, reformation of inflamed vaginal skin and surgical reconstruction of the urethra and bladder [521]. Such surgery requires specialist skills, best provided within a multi-disciplinary tertiary setting. Possible complications as a result of this surgical removal include bleeding, infection, damage to surrounding organs as well as lower urinary tract symptoms, persistent chronic pain and recurrent USI, which occurs after mesh removal [522]. Removal of mesh, whilst complex, does have beneficial outcomes generally, which are also durable particularly for chronic pain [523]. However, the long-term consequences after the mesh is removed still can include, not only chronic persistent pain but also autoimmune responses and complex neuropathies affecting the

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pelvis and the lower limbs [524, 525]. Some of these can be treated effectively using a multi-disciplinary pain medicine approach [526]. In other cases, the residual symptoms may require the input of an immunologist, rheumatologist or other symptom-defined specialist. The alternative to continence and prolapse mesh surgery is dependent on the clinical findings at the time. They include behavioural change, physiotherapy (for USI and Grade I-II uterovaginal prolapse) or traditional surgical techniques. Studies have shown that over 70% who committed to physiotherapy for stress urinary incontinence often did not need any further intervention [527]. Many clinicians are reverting to conservative measures first, before re-considering surgery. Clinicians are also now retraining in traditional continence surgical techniques, which existed in the pre-mesh era, such as the Burch colposuspension and autologous fascial sling; as well as traditional utero-vaginal prolapse techniques such as vaginal hysterectomy, sacrospinous fixation and fascial repair of vaginal wall prolapse.

5.4

Summary of evidence and recommendations: management

5.4.1

Management of primary prostate pain syndrome

Summary of evidence Phenotypically directed treatment may improve treatment success. α-blockers have moderate treatment effect regarding total pain, voiding, and QoL scores in PPPS. Antimicrobial therapy has a moderate effect on total pain, voiding, and QoL scores in PPPS. NSAIDs have moderate overall treatment effects on PPPS. Phytotherapy has some beneficial effect on pain and overall favourable treatment response in PPPS. Pentosane polysulphate improves global assessment and QoL score in PPPS. There are insufficient data on the effectiveness of muscle relaxants in PPPS. Pregabalin is not effective for the treatment of PPPS. BTX-A injection into the pelvic floor (or prostate) may have a modest effect in PPPS. Acupuncture is superior to sham acupuncture in improving symptoms and QoL. Posterior tibial nerve stimulation is probably effective for the treatment of PPPS. Extracorporeal shock wave therapy is probably effective over the short term. There are insufficient data supporting the use of other surgical treatments, such as transurethral incision of the bladder neck, transurethral resection of the prostate, or radical prostatectomy in patients with PPPS. Cognitive behavioural therapy designed for PPPS may improve pain and QoL. Recommendations Offer multimodal and phenotypically directed treatment options for Primary Prostate Pain Syndrome (PPPS). Use antimicrobial therapy (quinolones or tetracyclines) over a minimum of six weeks in treatment-naïve patients with a duration of PPPS less than one year. Use α-blockers for patients with a duration of PPPS less than one year. Offer high-dose oral pentosane polysulphate in PPPS. Offer acupuncture in PPPS. Offer non-steroidal anti-inflammatory drugs (NSAIDs) in PPPS, but long-term side-effects have to be considered. 5.4.2

3

Strength rating Weak Strong Strong Weak Strong Weak

Management of primary bladder pain syndrome

Summary of evidence There is insufficient data for the long-term use of corticosteroids. Limited data exist on effectiveness of cimetidine in PBPS. Amitriptyline is effective for pain and related symptoms of PBPS. Oral pentosane polysulphate is effective for pain and related symptoms of PBPS. Oral pentosane polysulphate plus subcutaneous heparin is effective for pain and related symptoms of PBPS, especially in initially low responders to pentosane polysulphate alone. Intravesical lidocaine plus sodium bicarbonate is effective in the short term. Intravesical pentosane polysulphate is effective, based on limited data, and may enhance oral treatment.

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There are limited data on the effectiveness of intravesical heparin. Intravesical chondroitin sulphate may be effective. There is insufficient data for the use of bladder distension as a therapeutic intervention. Hydrodistension plus BTX-A is superior to hydrodistension alone. Intravesical BCG is not effective in PBPS. Transurethral resection (coagulation and laser) may be effective in PBPS type 3 C. Sacral neuromodulation may be effective in PBPS. Pudendal nerve stimulation is superior to sacral neuromodulation for treatment of PBPS. Avoidance of certain foods and drink may reduce symptoms. Outcome of cystectomy for PBPS is variable.

Recommendations Offer subtype and phenotype-oriented therapy for the treatment of Primary Bladder Pain Syndrome (PBPS). Always consider offering multimodal behavioural, physical and psychological techniques alongside oral or invasive treatments of PBPS. Offer dietary advice. Administer amitriptyline for treatment of PBPS. Offer oral pentosane polysulphate for the treatment of PBPS. Offer oral pentosane polysulphate plus subcutaneous heparin in low responders to pentosane polysulphate alone. Do not recommend oral corticosteroids for long-term treatment. Offer intravesical hyaluronic acid or chondroitin sulphate before more invasive measures. Offer intravesical lidocaine plus sodium bicarbonate prior to more invasive methods. Offer intravesical heparin before more invasive measures alone or in combination treatment. Do not use bladder distension alone as a treatment of PBPS. Offer submucosal bladder wall and trigonal injection of botulinum toxin type A (BTX-A) plus hydrodistension if intravesical instillation therapies have failed. Offer neuromodulation before more invasive interventions. Only undertake ablative and/or reconstructive surgery as the last resort and only by experienced and PBPS-knowledgeable surgeons, following a multi-disciplinary assessment including pain management. Offer transurethral resection (or coagulation or laser) of bladder lesions, but in PBPS type 3 C only.

5.4.3

3 2b 3 1b 1b 3 3 1b 3 3

Strength rating Strong Strong Weak Strong Strong Weak Strong Weak Weak Weak Weak Strong Weak Strong

Strong

Management of scrotal pain syndrome

Summary of evidence Microsurgical denervation of the spermatic cord is an effective therapy for primary scrotal pain syndrome. Vasovasostomy is effective in post-vasectomy pain.

Recommendations Inform about the risk of post-vasectomy pain when counselling patients planned for vasectomy. Do open instead of laparoscopic inguinal hernia repair, to reduce the risk of scrotal pain. In patients with testicular pain improving after spermatic block, offer microsurgical denervation of the spermatic cord. 5.4.4

LE 2b 2b

Strength rating Strong Strong Weak

Management of primary urethral pain syndrome

Summary of evidence There is no specific treatment for primary urethral pain syndrome.

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5.4.5

Management of gynaecological aspects of chronic pelvic pain

Summary of evidence Therapeutic options, including pharmacotherapy and surgery, can treat endometriosis effectively. Psychological treatment (CBT or supportive psychotherapy) can improve pain and sexual and emotional function in vaginal and vulvar pain syndrome. Most gynaecological pain conditions (including dysmenorrhea, post-mesh insertion and gynaecological malignancy) can be treated effectively using pharmacotherapy. All other gynaecological conditions (including obstetric injury, pelvic organ prolapse) can be treated effectively using surgery. Recommendations Involve a gynaecologist to provide therapeutic options such as hormonal therapy or surgery in well-defined disease states. Provide a multi-disciplinary approach to pain management in persistent disease states. All patients who have developed complications after mesh insertion should be referred to a multi-disciplinary service (incorporating pain medicine and surgery). 5.4.6

3 2

Strength rating Strong Strong Strong

Management of primary anorectal pain syndrome

Summary of evidence Biofeedback is the preferred treatment for chronic primary anal pain syndrome. Electro-galvanic stimulation is less effective than biofeedback. Botulinum toxin type A is effective. Percutaneous tibial nerve stimulation is effective in anal pain. Sacral neuromodulation is effective in anal pain. Inhaled salbutamol is effective in intermittent chronic primary anal pain syndrome. Recommendations Undertake biofeedback treatment in patients with chronic anal pain. Offer botulinum toxin type A in chronic primary anal pain syndrome. Offer percutaneous tibial nerve stimulation in chronic primary anal pain syndrome. Offer sacral neuromodulation in chronic primary anal pain syndrome. Offer inhaled salbutamol in intermittent chronic primary anal pain syndrome. 5.4.7

LE 1b 1b

LE 1a 1b 1b 3 3 3 Strength rating Strong Weak Weak Weak Weak

Management of pudendal neuralgia

Summary of evidence There are multiple treatment options with varying levels of evidence.

LE 3

Recommendation Strength rating Neuropathic pain guidelines are well-established. Use standard approaches to management Strong of neuropathic pain.

5.4.8

Management of sexological aspects in chronic pelvic pain

Summary of evidence Pelvic floor muscle physical therapy may offer relief of pain and reduction in sexual complaints.

LE 2b

Recommendations Strength rating Offer behavioural strategies to the patient and his/her partner to reduce sexual dysfunctions. Weak Offer pelvic floor muscle therapy as part of the treatment plan to improve quality of life Weak and sexual function.

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5.4.9

Management of psychological aspects in chronic pelvic pain

Recommendation Strength rating For chronic pelvic pain with significant psychological distress, refer patient for chronic pelvic Strong pain-focused psychological treatment.

5.4.10

Management of pelvic floor dysfunction

Summary of evidence Myofascial treatment is effective. Biofeedback improves the outcome of myofascial therapy.

LE 1b 1a

Recommendations Strength rating Apply myofascial treatment as first-line treatment. Weak Offer biofeedback as therapy adjuvant to muscle exercises, in patients with anal pain due to Strong an overactive pelvic floor. 5.4.11

Management of chronic/non-acute urogenital pain by opioids

Recommendations Opioids and other drugs of addiction/dependency should only be prescribed following multi-disciplinary assessment and only after other reasonable treatments have been tried and failed. The decision to instigate long-term opioid therapy should be made by an appropriatelytrained specialist in consultation with the patient and their family doctor. Where there is a history or suspicion of drug abuse, involve a psychiatrist or psychologist with an interest in pain management and drug addiction.

Strength rating Strong

Strong Strong

6.

EVALUATION OF TREATMENT RESULTS

6.1

Evaluation of treatment

For patients with chronic primary visceral pain, a visit to the clinician is important because they can ask questions, talk about how the process is going and have some time with the caregiver who understands the nature of their pain. First evaluation should take place after about six weeks to see if the treatment has been successful or not. When necessary adaptations are made and a next evaluation is planned. 6.1.1 Treatment has not been effective 6.1.1.1 Alternative treatment In cases where the treatment initiated did not have enough effect, an alternative approach is advised. The first thing to do is a thorough evaluation of the patients’ or care providers’ adherence to the treatment that was initiated. Ask the patient if they have taken the medication according to the prescription, if there were any sideeffects and if there were any changes in pain and function. Adjustment of medication or dose schemes might help. Another important thing to do is to read the reports of other caregivers, for example, the physiotherapist and the psychologist. Has the therapy been followed until the end, what was the opinion of the therapist about the changes that were observed? In cases where the sessions had been terminated by the patient, ask the patient why they made that decision. Check if the patient has understood the idea behind the therapy that had been prematurely stopped. 6.1.1.2 Referral to next envelope of care If patients and doctors conclude that none of the therapies given showed enough effect, then referral to a next envelope of care is advised. Unfortunately, the terminology used to describe the nature and specialisation level of centres providing specialised care for visceral pain patients is not standardised and is country-based. This does not facilitate easy referral schemes. It is advised that patients are referred to a centre that is working with

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a multi-disciplinary team and nationally recognised as specialised in pelvic pain. Such a centre will re-evaluate what has been done and when available, provide specialised care. 6.1.1.3 Self-management and shared care Patients who find themselves confronted with CPPPS, for which there is no specific treatment option available, will have to live with their pain. They will need to manage their pain, meaning that they will have to find a way to deal with the impact of their pain on daily activities in all domains of life. Self-help programmes may be advised and can be of help. The patient may also benefit from shared care, which means that a caregiver is available for supporting the self-management strategies. Together with this caregiver, the patient can optimise and use the management strategies. 6.1.2 Treatment has been effective In cases where treatment has been effective, the caregiver may pay attention to fall-back prevention. If the patient feels the same pain again, it helps to start at an early stage with the self-management strategies that he/she has learned during the former treatment. By doing so they will have the best chance of preventing the re-development of pelvic pain syndromes.

7.

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8.

CONFLICT OF INTEREST

All members of the EAU Chronic Pelvic Pain Guidelines working panel have provided disclosure statements on all relationships that they have that might be perceived to be a potential source of conflict of interest. This information is publically accessible through the European Association of Urology website http://www.uroweb. org/guidelines/. This document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

9.

CITATION INFORMATION

The format in which to cite the EAU Guidelines will vary depending on the style guide of the journal in which the citation appears. Accordingly, the number of authors or whether, for instance, to include the publisher, location, or an ISBN number may vary. The compilation of the complete Guidelines should be referenced as: EAU Guidelines. Edn. presented at the EAU Annual Congress Milan 2021. ISBN 978-94-92671-13-4. If a publisher and/or location is required, include: EAU Guidelines Office, Arnhem, The Netherlands. http://uroweb.org/guidelines/compilations-of-all-guidelines/ References to individual guidelines should be structured in the following way: Contributors’ names. Title of resource. Publication type. ISBN. Publisher and publisher location, year.

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EAU Guidelines on

Neuro-Urology B. Blok (Chair), D. Castro-Diaz, G. Del Popolo, J. Groen, R. Hamid, G. Karsenty, T.M. Kessler, J. Pannek (Vice-chair) Guidelines Associates: H. Ecclestone, S. Musco, B. Padilla-Fernández, A. Sartori, L.A. ‘t Hoen

© European Association of Urology 2020

TABLE OF CONTENTS

PAGE

1. INTRODUCTION 1.1 Aim and objectives 1.2 Panel composition 1.3 Available publications 1.4 Publication history 1.5 Background

4 4 4 4 4 4

2.

4 4 5

METHODS 2.1 Introduction 2.2 Review

3. THE GUIDELINE 5 3.1 Epidemiology, aetiology and pathophysiology 5 3.1.1 Introduction 5 3.2 Classification systems 7 3.2.1 Introduction 7 3.3 Diagnostic evaluation 7 3.3.1 Introduction 7 3.3.2 Classification systems 8 3.3.3 Timing of diagnosis and treatment 8 3.3.4 Patient history 8 3.3.4.1 Bladder diaries 9 3.3.5 Patient quality of life questionnaires 10 3.3.5.1 Available Questionnaires 10 3.3.6 Physical examination 11 3.3.6.1 Autonomic dysreflexia 11 3.3.6.2 Summary of evidence and recommendations for history taking and physical examination 12 3.3.7 Urodynamics 13 3.3.7.1 Introduction 13 3.3.7.2 Urodynamic tests 13 3.3.7.3 Specialist uro-neurophysiological tests 14 3.3.7.4 Summary of evidence and recommendations for urodynamics and uro-neurophysiology 14 3.3.8 Renal function 14 3.4 Disease management 15 3.4.1 Introduction 15 3.4.2 Non-invasive conservative treatment 15 3.4.2.1 Assisted bladder emptying - Credé manoeuvre, Valsalva manoeuvre, triggered reflex voiding 15 3.4.2.2 Neuro-urological rehabilitation 15 3.4.2.2.1 Bladder rehabilitation including electrical stimulation 15 3.4.2.3 Drug treatment 16 3.4.2.3.1 Drugs for storage symptoms 16 3.4.2.3.2 Drugs for voiding symptoms 17 3.4.2.4 Summary of evidence and recommendations for drug treatments 17 3.4.2.5 Minimally invasive treatment 17 3.4.2.5.1 Catheterisation 17 3.4.2.5.2 Summary of evidence and recommendations for catheterisation 18 3.4.2.5.3 Intravesical drug treatment 18 3.4.2.5.4 Summary of evidence and recommendations for intravesical drug treatment 18 3.4.2.5.5 Botulinum toxin injections in the bladder 18 3.4.2.5.6 Bladder neck and urethral procedures 19 3.4.2.5.7 Summary of evidence and recommendations for botulinum toxin A injections and bladder neck procedures 19 3.4.3 Surgical treatment 19

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3.4.3.1 Bladder neck and urethral procedures 3.4.3.2 Denervation, deafferentation, sacral neuromodulation 3.4.3.3 Bladder covering by striated muscle 3.4.3.4 Bladder augmentation 3.4.3.5 Urinary diversion 3.4.3.6 Summary of evidence and recommendations for surgical treatment 3.5 Urinary tract infection in neuro-urological patients 3.5.1 Epidemiology, aetiology and pathophysiology 3.5.2 Diagnostic evaluation 3.5.3 Disease management 3.5.3.1 Recurrent UTI 3.5.3.2 Prevention 3.5.4 Summary of evidence and recommendations for the treatment of UTI 3.6 Sexual function and fertility 3.6.1 Erectile dysfunction 3.6.1.1 Phosphodiesterase type 5 inhibitors (PDE5Is) 3.6.1.2 Drug therapy other than PDE5Is 3.6.1.3 Mechanical devices 3.6.1.4 Intracavernous injections and intraurethral application 3.6.1.5 Sacral neuromodulation 3.6.1.6 Penile prostheses 3.6.1.7 Summary of evidence and recommendations for erectile dysfunction 3.6.2 Male fertility 3.6.2.1 Sperm quality and motility 3.6.2.2 Summary of evidence and recommendations for male fertility 3.6.3 Female sexuality 3.6.4 Female fertility 3.6.4.1 Summary of evidence and recommendation for female sexuality and fertility 3.7 Follow-up 3.7.1 Introduction 3.7.2 Summary of evidence and recommendations for follow-up 3.8 Conclusions

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REFERENCES

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CONFLICT OF INTEREST

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CITATION INFORMATION

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19 21 21 21 21 22 22 22 23 23 23 23 24 24 24 24 24 25 25 25 25 25 25 26 26 26 27

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1.

INTRODUCTION

1.1

Aim and objectives

The European Association of Urology (EAU) Neuro-Urology Guidelines aim to provide information for clinical practitioners on the incidence, definitions, diagnosis, therapy, and follow-up of neuro-urological disorders. These Guidelines reflect the current opinion of experts in this specific pathology and represent a state-of-the art reference for all clinicians, as of the publication date. The terminology used and the diagnostic procedures advised throughout these Guidelines follow the recommendations for investigations of the lower urinary tract (LUT) as published by the International Continence Society (ICS) [1-3]. Readers are advised to consult other EAU Guidelines that may address different aspects of the topics discussed in this document. It must be emphasised that clinical guidelines present the best evidence available to the experts but following guideline recommendations will not necessarily result in the best outcome. Guidelines can never replace clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions - also taking personal values and preferences/individual circumstances of patients into account. Guidelines are not mandates and do not purport to be a legal standard of care.

1.2

Panel composition

The EAU Neuro-Urology Guidelines Panel consists of an international multidisciplinary group of neurourological experts. All experts involved in the production of this document have submitted potential conflict of interest statements which can be viewed on the EAU website: http://www.uroweb.org/guideline/neuro-urology/.

1.3

Available publications

A quick reference document, the Pocket Guidelines, is available in print and as an app for iOS and Android devices. These are abridged versions which may require consultation with the full text version. A guideline summary has also been published in European Urology [4]. All are available through the EAU website: ­http://www.uroweb.org/guideline/neurourology/.

1.4

Publication history

The EAU published the first Neuro-Urology Guidelines in 2003 with updates in 2008, 2014, and 2017. This 2020 document represents a limited update of the 2019 publication. The literature was assessed for all chapters.

1.5

Background

The function of the LUT is mainly storage and voiding of urine, which is regulated by the nervous system that coordinates the activity of the urinary bladder and bladder outlet. The part of the nervous system that regulates LUT function is disseminated from the peripheral nerves in the pelvis to highly specialised cortical areas. Any disturbance of the nervous system involved, can result in neuro-urological symptoms. The extent and location of the disturbance will determine the type of LUT dysfunction, which can be symptomatic or asymptomatic. Neuro-urological symptoms can cause a variety of long-term complications; the most significant being deterioration of renal function. Since symptoms and long-term complications do not correlate [5], it is important to identify patients with neuro-urological symptoms, and establish if they have a low or high risk of subsequent complications. The risk of developing upper urinary tract (UUT) damage and renal failure is much lower in patients with slowly progressive non-traumatic neurological disorders than in those with spinal cord injury or spina bifida [6]. In summary, treatment and intensity of follow-up examinations are based on the type of neurourological disorder and the underlying cause.

2.

METHODS

2.1

Introduction

For the 2020 Neuro-Urology Guidelines, new and relevant evidence has been identified, collated and appraised through a structured assessment of the literature. A broad and comprehensive literature search, covering all sections of the Neuro-Urology Guidelines was performed. Databases searched included Medline, EMBASE, and the Cochrane Libraries, covering a time frame between May 31st 2018 and 1st April 2019. A total of 754 unique records were identified, retrieved and screened for relevance. A detailed search strategy is available online: http://uroweb.org/guideline/neuro-urology/?type=appendices-publications.

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For each recommendation within the guidelines there is an accompanying online strength rating form, the bases of which is a modified GRADE methodology [7, 8]. Each strength rating form addresses a number of key elements namely: 1. the overall quality of the evidence which exists for the recommendation, references used in this text are graded according to a classification system modified from the Oxford Centre for Evidence-Based Medicine Levels of Evidence [9]; 2. the magnitude of the effect (individual or combined effects); 3. the certainty of the results (precision, consistency, heterogeneity and other statistical or study related factors); 4. the balance between desirable and undesirable outcomes; 5. the impact of patient values and preferences on the intervention; 6. the certainty of those patient values and preferences. These key elements are the basis which panels use to define the strength rating of each recommendation. The strength of each recommendation is represented by the words ‘strong’ or ‘weak’ [10]. The strength of each recommendation is determined by the balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including certainty of estimates), and nature and variability of patient values and preferences. Additional information can be found in the general Methodology section of this print, and online at the EAU website; http://www.uroweb.org/guideline/. A list of associations endorsing the EAU Guidelines can also be viewed online at the above address.

2.2

Review

Publications ensuing from panel-led systematic reviews have all been peer-reviewed. The 2015 Neuro-Urology Guidelines were subject to peer review prior to publication.

3.

THE GUIDELINE

3.1

Epidemiology, aetiology and pathophysiology

3.1.1 Introduction Neuro-urological symptoms may be caused by a variety of diseases and events affecting the nervous system controlling the LUT. The resulting neuro-urological symptoms depend predominantly on the location and the extent of the neurological lesion. There are no exact figures on the overall prevalence of neuro-urological disorders in the general population, but data are available on the prevalence of the underlying conditions and the relative risk of these for the development of neuro-urological symptoms. It is important to note that the majority of the data shows a very wide range of prevalence/incidence. This reflects the variability in the cohort (e.g. early or late stage disease) and the frequently small sample sizes, resulting in a low level of evidence in most published data (summarised in Table 1).

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Table 1: Epidemiology of Neuro-Urological Disorders Suprapontine and pontine lesions and diseases Neurological Disease Frequency in General Population Type and Frequency of NeuroUrological Symptoms Cerebrovascular accident 450 cases/100,000/yr (Europe) [11], Nocturia - overactive bladder (OAB) (Strokes) 10% of cardiovascular mortality. - urgency urinary incontinence (UUI) - detrusor overactivity (DO), other patterns less frequent [12]. 57-83% of neuro-urological symptoms at 1 month post-stroke, 71-80% spontaneous recovery at 6 months [13]. Persistence of urinary incontinence (UI) correlates with poor prognosis [14]. 6.4% of adults > 65 yrs [15]. OAB - UUI – DO 25% of Dementias: incontinence in Alzheimer’s Alzheimer’s disease (80%), disease, > 25% in other dementias: Vascular (10%), Other (10%). Lewy body, NPH, Binswanger, Nasu-Hakola, Pick Disease [16]. Incontinence 3 times more frequent in geriatric patients with dementia than without [17]. Urinary symptoms affect 50% Second most prevalent Parkinsonian syndrome (PS) at onset, with urgency and neurodegenerative disease after Idiopathic Parkinson’s disease nocturia being the most common. Alzheimer’s disease. (IPD): 75-80% of PS. Rising prevalence of IPD with age Patients with urinary symptoms at presentation have worse disease [18]. progression in Parkinson’s disease [19]. Non-IPD: Parkinson’s-plus (18%): MSA is the most frequent non-IPD - Multiple system atrophy (MSA), PS. - Progressive supranuclear palsy, - Corticobasal degeneration, - Dementia with Lewy bodies. Secondary Parkinson’s (2%) Brain tumours

Cerebral palsy

Traumatic brain injury

Normal pressure hydrocephalus

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Infections account for a major cause of mortality in MSA [20].

Impaired detrusor contractility with post-void residual (PVR) > 150 mL seems to be the urodynamic finding distinguishing MSA from IPD [21-23]. 26.8/100,000/yr in adults (> 19 yrs), Incontinence occurs mainly in frontal (17.9 benign, 8.9 malignant) [24]. location (part of frontal syndrome or isolated in frontal location) [25]. Cerebral palsy: 3.1-3.6/1,000 in 46% of patients with cerebral palsy children aged 8 yrs [26]. suffer from UI, with 85% of patients having abnormal urodynamic studies (NDO most common 59%). Upper tract deterioration is rare (2.5%) [27]. 235/100,000/yr [28]. 44% storage dysfunction, 38% voiding dysfunction, 60% urodynamic abnormalities [29]. 0.5% of the population > 60, up to Classic triad of gait and cognitive 2.9% of those > 65 [30]. disturbance along with UI. Incontinence affects 98-100% of patients [30].

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Lesions and diseases between caudal brainstem and sacral spinal cord Neurogenic detrusor overactivity Spinal cord injury (SCI) Prevalence of traumatic SCI in (NDO) and detrusor sphincter developed countries ranges from dyssynergia (DSD) (up to 95%) and 280 to 906/million [31]. detrusor underactivity (up to 83%) depending on the level of the lesion [32]. Bladder function is impaired in up Spina bifida (SB) Spina bifida 3-4/10,000 Lumbar and lumbosacral form are to 96% of SB patients [34]. Over 50% of patients are incontinent the most common (60%) [33]. [35]. Patients with open and closed defects can have equally as severe neurogenic lower urinary tract dysfunction [36]. Lesions and diseases of the peripheral nervous system Male (5%) and female (3%) > 35 yr 26% difficulty to void and Lumbar spine acontractile detrusor [37]. have had a lumbosciatic Degenerative disease Detrusor underactivity (up to 83%) episode related to disc prolapse. Disk prolapse [32]. Lumbar canal stenosis Tarlov cysts: early sensation of filling (70%), NDO (33%), urethral instability (33%) and stress urinary incontinence (SUI) (33%) [38]. After abdomino-perineal resection: Rectal cancer. 50% urinary retention. Cervical cancer (multimodal therapy, radiotherapy and surgery). After total mesorectal excision: 10-30% voiding dysfunction [39]. Endometriosis surgery. Urgency/frequency +/- incontinence Worldwide, prevalence of pharmacologically treated diabetes [41]. Hyposensitive and detrusor 8.3% [40]. underactivity at later phase [41]. Incidence: approx. 5/100,000/yr More common in females > 45 yr.

Iatrogenic pelvic nerve lesions

Peripheral neuropathy Diabetes Other causes of peripheral neuropathy causing neurourological symptoms: alcohol abuse; lumbosacral zona and genital herpes; Guillain Barré syndrome. Disseminated central diseases Multiple sclerosis (MS)

3.2

Prevalence: 83/100,000 in Europe [42].

10% of MS patients present with voiding dysfunction at disease onset, 75% of patients will develop it after 10 yrs of MS [43]. DO: 86% [43]. DSD: 35% [43]. Detrusor underactivity: 25% [43].

Classification systems

3.2.1 Introduction Relevant definitions can be found in the general ICS standardisation reports [2, 3, 44]. Supplementary online Tables S1 and S2 list the definitions from these references, partly adapted, and other definitions considered useful for clinical practice: https://uroweb.org/guideline/neuro-urology/?type=appendices-publications.

3.3

Diagnostic evaluation

3.3.1 Introduction The normal physiological function of the LUT depends on an intricate interplay between the sensory and motor nervous systems. When diagnosing neuro-urological symptoms, the aim is to describe the type of dysfunction involved. A thorough medical history, physical examination and bladder diary are mandatory before any additional diagnostic investigations can be planned. Results of the initial evaluation are used to decide the patient’s long-term treatment and follow-up.

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3.3.2 Classification systems The pattern of LUT dysfunction following neurological disease is determined by the site and nature of the lesion. A very simple classification system for use in daily clinical practice to decide on the appropriate therapeutic approach is provided in Figure 1 [6]. Figure 1: Patterns of lower urinary tract dysfunction following neurological disease

(A)

(B)

(C)

The pattern of LUT dysfunction following neurological disease is determined by the site and nature of the lesion. Panel (A) denotes the region above the pons, panel (B) the region between the pons and the sacral cord and panel (C) the sacral cord and infrasacral region. Figures on the right show the expected dysfunctional states of the detrusor-sphincter system. Figure adapted from Panicker et al. [6] with permission from Elsevier. PVR = post-void residual. 3.3.3 Timing of diagnosis and treatment Early diagnosis and treatment are essential in both congenital and acquired neuro-urological disorders [45]. This helps to prevent irreversible changes within the LUT, even in the presence of normal reflexes [46, 47]. Furthermore, urological symptoms can be the presenting feature of neurological pathology [48, 49]. Early intervention can prevent irreversible deterioration of the LUT and UUT [50]. Long term follow up (life-long) is mandatory to assess risk of UUT damage, renal failure and bladder cancer [51-53]. 3.3.4 Patient history History taking should include past and present symptoms and disorders (Table 4). It is the cornerstone of evaluation, as the answers will aid selection of diagnostic investigations and treatment options. • • •

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In non-traumatic neuro-urological patients with an insidious onset, a detailed history may find that the condition started in childhood or adolescence [54]. Urinary history consists of symptoms associated with both urine storage and voiding. Bowel history is important because patients with neuro-urological symptoms may also have related neurogenic bowel dysfunction [55].

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• • • • •

Sexual function may be impaired because of the neuro-urological condition [56]. Special attention should be paid to possible warning signs and symptoms (e.g. pain, infection, haematuria and fever) requiring further investigation. Patients with SCI usually find it difficult to report urinary tract infection (UTI)-related symptoms accurately [57, 58]. The presence of urinary, bowel and sexual symptoms without neurological symptoms could be suggestive of an underlying neurological disease or condition. Ambulatory status after acute SCI does not predict presence or absence of unfavourable urodynamic parameters [59].

Table 4: History taking in patients with suspected neuro-urological disorder Past history Childhood through to adolescence and into adulthood Hereditary or familial risk factors Specific female: menarche (age); this may suggest a metabolic disorder Obstetric history History of diabetes Diseases, e.g. multiple sclerosis, parkinsonism, encephalitis, syphilis Accidents and operations, especially those involving the spine and central nervous system Present history Present medication Lifestyle (smoking, alcohol and drugs); may influence urinary, sexual and bowel function Quality of life Specific urinary history Onset of urological history Relief after voiding; to detect the extent of a neurological lesion in the absence of obstructive uropathy Bladder sensation Initiation of micturition (normal, precipitate, reflex, strain, Credé) Interruption of micturition (normal, paradoxical, passive) Enuresis Mode and type of voiding (catheterisation) Frequency, voided volume, incontinence, urgency episodes Sexual history Genital or sexual dysfunction symptoms Sensation in genital area Specific male: erection, (lack of) orgasm, ejaculation Specific female: dyspareunia, (lack of) orgasm Bowel history Frequency and faecal incontinence Desire to defecate Defecation pattern Rectal sensation Initiation of defecation (digitation) Neurological history Acquired or congenital neurological condition Mental status and comprehension Neurological symptoms (somatic and sensory), with onset, evolution and any treatment Spasticity or autonomic dysreflexia (especially in lesions at or above level Th 6) Mobility and hand function 3.3.4.1 Bladder diaries Bladder diaries provide data on the number of voids, voided volume, pad weight and incontinence and urgency episodes [3, 60]. Although a 24-hour bladder diary (recording should be done for three consecutive days) is reliable in women with UI [61, 62], no research has been done on bladder diaries in neuro-urological patients. Nevertheless, bladder diaries are considered a valuable diagnostic tool.

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3.3.5 Patient quality of life questionnaires An assessment of the patient’s present and expected future quality of life (QoL) is important to evaluate the effect of any therapy. Quality of life is an essential aspect of the overall management of neuro-urological patients, for example when evaluating treatment related changes on a patient’s QoL [63]. The type of bladder management has been shown to affect health-related QoL (HRQoL) in patients with SCI [64, 65] and MS [66], as does the presence or absence of urinary and faecal incontinence [67]. Other research has also highlighted the importance of urological treatment and its impact on the urodynamic functionality of the neuro-urological patient in determining patient QoL [68]. In recent years a proliferation in the number of questionnaires to evaluate symptoms and QoL has been seen. Condition-specific questionnaires can be used to assess symptom severity and the impact of symptoms on QoL. A patient’s overall QoL can be assessed using generic questionnaires. It is important that the questionnaire of choice has been validated in the neuro-urological population, and that it is available in the language that it is to be used in. 3.3.5.1 Available Questionnaires Three condition-specific questionnaires for urinary or bowel dysfunction and QoL have been developed specifically for adult neuro-urological patients [69]. In MS and SCI patients the Qualiveen [70, 71] is validated and can be used for urinary symptoms. A short form of the Qualiveen is available [70, 71] and it has been translated into various languages [72-77]. Although several objective and subjective tools have been used to assess the influence of neurogenic bladder on QoL in SCI, the Quality life index-SCI and Qualiveen are the only validated condition-specific outcomes that have shown consistent sensitivity to neurogenic bladder [78]. The Neurogenic Bladder Symptom Score (NBSS) has been validated in neurological patients to measure urinary symptoms and their consequences [79, 80]. The QoL scoring tool related to Bowel Management (QoL-BM) [81] can be used to assess bowel dysfunction in MS and SCI patients. In addition, sixteen validated questionnaires that evaluate QoL and asses urinary symptoms as a subscale or question in neuro-urological patients have been identified [82, 83] (Table 5). The condition-specific Incontinence-Quality of Life (I-QoL) questionnaire which was initially developed for the non-neurological population has now also been validated for neuro-urological patients [84]. A patient’s overall QoL can be assessed by generic HRQoL questionnaires, the most commonly used being the I-QOL, King’s Health Questionnaire (KHQ), or the Short Form 36-item and 12-item Health Survey Questionnaires (SF-36, SF-12) [69]. In addition, the quality-adjusted life year (QALY), quantifies outcomes, by weighing years of life spent in a specified health state, adjusted by a factor representing the value placed by society or patients on their specific health state [85]. No evidence was found for which validated questionnaires are the most appropriate for use, since no quality criteria for validated questionnaires have been assessed [69]. Table 5: Patient questionnaires Questionnaire FAMS [86] FILMS [87] HAQUAMS [88] I-QOL [84] MDS [89] MSISQ-15 / MSISQ-19 [90, 91] MSQLI [92] MSQoL-54 [93] MSWDQ [94] NBSS [95] QoL-BM [81] Qualiveen/SF-Qualiveen [71, 96] RAYS [97] RHSCIR [98] Fransceschini [97]

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Underlying neurological disorder MS MS MS MS, SCI MS MS MS MS MS MS, SCI, Congenital neurogenic bladder SCI MS, SCI MS SCI SCI

Bladder X X X X X X X X X X

Bowel

Sexual function X

X X X X X X X

X X X X X

X X X X X

X X

X X X X

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3.3.6 Physical examination In addition to a detailed patient history, attention should be paid to possible physical and intellectual disabilities with respect to the planned investigations [99, 100]. Neuro-urological status should be described as completely as possible (Figure 2) [6]. Patients with a high spinal cord lesion or supraspinal neurological lesions may suffer from a significant drop in blood pressure when moved into a sitting or standing position. All sensations and reflexes in the urogenital area must be tested [6]. Furthermore, detailed testing of the anal sphincter and pelvic floor functions must be performed (Figure 2) [6, 101]. It is essential to have this clinical information to reliably interpret later diagnostic investigations. Additionally, urinalysis, blood chemistry, ultrasonography, residual and free flowmetry and incontinence quantification should be performed as part of the routine assessment of neuro-urological patients [6, 102]. 3.3.6.1 Autonomic dysreflexia Autonomic dysreflexia (AD) is a sudden and exaggerated autonomic response to various stimuli in patients with SCI or spinal dysfunction. It generally manifests at or above level Th 6. The stimulus can be distended bladder or bowel. For example, iatrogenic stimuli during cystoscopy or urodynamics can trigger AD [103]. It can also be secondary to sexual stimulation or a noxious stimulus, e.g. infected toe nail or pressure sore. Autonomic dysreflexia is defined by an increase in systolic blood pressure > 20 mmHg from baseline [104] and can have life-threatening consequences if not properly managed. Figure 2: Lumbosacral dermatomes, cutaneous nerves, and reflexes

The physical examination includes testing sensations and reflexes mediated through the lower spinal cord. Abnormal findings would suggest a lesion affecting the lumbosacral segments; mapping out distinct areas of sensory impairment helps to further localise the site of the lesion. Distribution of dermatomes (areas of skin mainly supplied by a single spinal nerve) and cutaneous nerves over the perianal region and back of the upper thigh (A), the perineum [105] (B), male external genitalia [106] (C) and root values of lower spinal cord reflexes (D). Figure adapted from Panicker et al. [6] with parts A-C adapted from Standring [107], both with permission from Elsevier.

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Table 6: Neurological items to be specified Sensation S2-S5 (both sides) Presence (increased/normal/reduced/absent) Type (light touch/pin prick) Affected dermatomes Reflexes (increased/normal/reduced/absent) Bulbocavernous reflex Perianal/anal reflex Knee and ankle reflexes Plantar responses (Babinski) Anal sphincter tone Presence (increased/normal/reduced/absent) Voluntary contractions of anal sphincter and pelvic muscles (increased/normal/reduced/absent) Prostate palpation Descensus (prolapse) of pelvic organs 3.3.6.2

Summary of evidence and recommendations for history taking and physical examination

Summary of evidence Early diagnosis and treatment are essential in both congenital and acquired neuro-urological disorders to prevent irreversible changes within the LUT. An extensive general history is the basis of evaluation focusing on past and present symptoms including urinary, sexual, bowel and neurological functions. Assessment of present and expected future QoL is an essential aspect of the overall management of neuro-urological patients and is important to evaluate the effect of any therapy. Quality of life assessment should be completed with validated QoL questionnaires for neuro-urological patients. Bladder diaries provide data on the number of voids, voided volume, pad weight and incontinence and urgency episodes.

LE 4 4 2a 1a 3

Recommendations Strength rating History taking Take an extensive general history, concentrating on past and present symptoms. Strong Take a specific history for each of the four mentioned functions - urinary, bowel, sexual and Strong neurological. Pay special attention to the possible existence of alarm signs (e.g. pain, infection, Strong haematuria, fever) that warrant further specific diagnosis. Assess quality of life when evaluating and treating the neuro-urological patient. Strong Strong Use available validated tools including the Qualiveen and I-QoL for urinary symptoms and the QoL-BM for bowel dysfunction in multiple sclerosis and spinal cord injury patients. In addition, generic (SF-36 or KHQ) questionnaires can be used. Use MSISQ-15 and MSISQ-19 to evaluate sexual function in multiple sclerosis patients. Strong Physical examination Acknowledge individual patient disabilities when planning further investigations. Strong Describe the neurological status as completely as possible, sensations and reflexes in the Strong urogenital area must all be tested. Test the anal sphincter and pelvic floor functions. Strong Perform urinalysis, blood chemistry, bladder diary, residual and free flowmetry, incontinence Strong quantification and urinary tract imaging. I-QoL = Incontinence Quality of Life Instrument; QoL-BM = Quality of Life Bowel Management scoring tool; KHQ = King’s Health Questionnaire; SF-36 = Short Form 36-item Health Survey Questionnaires; MSISQ 15/19 = Multiple Sclerosis Intimacy and Sexuality Questionnaire 15/19 question version.

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3.3.7 Urodynamics 3.3.7.1 Introduction Urodynamic investigation is the only method that can objectively assess the function and dysfunction of the LUT. In neuro-urological patients, invasive urodynamic investigation is even more challenging than in general patients. Any technical source of artefacts must be critically considered. It is essential to maintain the quality of the urodynamic recording and its interpretation [1]. Same session repeat urodynamic investigations are crucial in clinical decision making, since repeat measurements may yield completely different results [108]. In patients at risk of AD, it is advisable to measure blood pressure during the urodynamic study [109, 110]. The rectal ampulla should be empty of stool before the start of the investigation. All urodynamic findings must be reported in detail and performed, according to the ICS technical recommendations and standards [1, 111]. 3.3.7.2 Urodynamic tests Free uroflowmetry and assessment of residual urine: Provides a first impression of the voiding function and is compulsory prior to planning any invasive urodynamics in patients able to void. For reliable information, it should be repeated at least two to three times [1]. Possible pathological findings include a low flow rate, low voided volume, intermittent flow, hesitancy and residual urine. Care must be taken when assessing the results in patients unable to void in a normal position, as both flow pattern and rate may be modified by inappropriate positions. Filling cystometry: This test is the only method for quantifying the patient’s filling function. The status of LUT (C) function must be documented during the filling phase. However, this technique has limited use as a solitary procedure. It is much more effective combined with bladder pressure measurement during micturition and is even more effective in video-urodynamics. The bladder should be empty at the start of filling. A physiological filling rate should be used with body-warm saline. Possible pathological findings include DO, low bladder compliance, abnormal bladder sensations, incontinence, and an incompetent or relaxing urethra. There is some evidence that a bladder capacity < 200 mL and detrusor pressures over 75 cm H2O are independent risk factors for UUT damage in patients with SCI [51]. Detrusor leak point pressure [112]: Appears to have no use as a diagnostic tool. Some positive findings have been reported [113-115], but sensitivity is too low to estimate the risk to the UUT or for secondary bladder damage [116, 117]. Pressure flow study: Reflects the coordination between detrusor and urethra or pelvic floor during the voiding phase. It is even more effective if combined with filling cystometry and video-urodynamics. Lower urinary tract function must be recorded during the voiding phase. Possible pathological findings include detrusor underactivity, bladder outlet obstruction (BOO), DSD, a high urethral resistance, and residual urine. Most types of obstruction caused by neuro-urological disorders are due to DSD [118, 119], nonrelaxing urethra, or non-relaxing bladder neck [120, 121]. Pressure-flow analysis mainly assesses the amount of mechanical obstruction caused by the urethra’s inherent mechanical and anatomical properties and has limited value in patients with neuro-urological disorders. Electromyography (EMG): Reflects the activity of the external urethral sphincter, the peri-urethral striated musculature, the anal sphincter and the striated pelvic floor muscles. Correct interpretation may be difficult due to artefacts introduced by other equipment. In the urodynamic setting, an EMG is useful as a gross indication of the patient’s ability to control the pelvic floor. Possible pathological findings include inadequate recruitment upon specific stimuli (e.g. bladder filling, involuntary detrusor contractions, onset of voiding, coughing, Valsalva manoeuvre) suggesting a diagnosis of DSD [122]. Urethral pressure measurement: Has a very limited role in neuro-urological disorders. There is no consensus on parameters indicating pathological findings [123]. Video-urodynamics: Is the combination of filling cystometry and pressure flow studies with imaging. It is the optimum procedure for urodynamic investigation in neuro-urological disorders [5]. Possible pathological findings include all those described in the cystometry and the pressure flow study sections, and any morphological pathology of the LUT and reflux to the UUT [124]. Ambulatory urodynamics: This is the functional investigation of the urinary tract, which predominantly uses the natural filling of the urinary tract to reproduce the patient’s normal activity. Although this type of study might be

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considered when conventional urodynamics does not reproduce the patient’s symptoms, its role in the neurourological patient still needs to be determined [125, 126]. Triggered tests during urodynamics: Lower urinary tract function can be provoked by coughing, triggered voiding, or anal stretch. Fast-filling cystometry with cooled saline (the ‘ice water test’) will discriminate between upper and lower motor neuron lesions [127, 128]. Patients with upper motor neuron lesions develop a detrusor contraction if the detrusor is intact, while patients with lower motor neuron lesions do not. However, the test does not seem to be fully discriminative in other types of patients [129]. Previously, a positive bethanechol test [130] (detrusor contraction > 25 cm H2O) was thought to indicate detrusor denervation hypersensitivity and the muscular integrity of an acontractile detrusor. However, in practice, the test has given equivocal results. A variation of this method was reported using intravesical electromotive administration of the bethanechol [131], but there was no published follow-up. Currently, there is no indication for this test. 3.3.7.3 Specialist uro-neurophysiological tests The following tests are advised as part of the neurological work-up [132]: • electromyography (in a neurophysiological setting) of pelvic floor muscles, urethral sphincter and/or anal sphincter; • nerve conduction studies of pudendal nerve; • reflex latency measurements of bulbocavernosus and anal reflex arcs; • evoked responses from clitoris or glans penis; • sensory testing on bladder and urethra. Other elective tests, for specific conditions, may become obvious during the work-up and urodynamic investigations. 3.3.7.4

Summary of evidence and recommendations for urodynamics and uro-neurophysiology

Summary of evidence Urodynamic investigation is the only method that can objectively assess the (dys-)function of the LUT. Video-urodynamics is the optimum procedure for urodynamic investigation in neuro-urological disorders. Specific uro-neurophysiological tests are elective procedures and should only be carried out in specialised settings.

Recommendations Perform a urodynamic investigation to detect and specify lower urinary tract (dys-)function, use same session repeat measurement as it is crucial in clinical decision making. Non-invasive testing is mandatory before invasive urodynamics is planned. Use video-urodynamics for invasive urodynamics in neuro-urological patients. If this is not available, then perform a filling cystometry continuing into a pressure flow study. Use a physiological filling rate and body-warm saline.

LE 2a 4 4

Strength rating Strong Strong Strong Strong

3.3.8 Renal function In many patients with neuro-urological disorders, the UUT is at risk, particularly in patients who develop high detrusor pressure during the filling phase. Although effective treatment can reduce this risk, there is still a relatively high incidence of renal morbidity [133, 134]. Patients with SCI or SB have a higher risk of developing renal failure compared with patients with slowly progressive non-traumatic neurological disorders, such as MS and Parkinson’s disease (PD) [135]. Caregivers must be informed of this risk and instructed to watch carefully for any signs or symptoms of a possible deterioration in the patient’s renal function. In patients with poor muscle mass cystatin C based glomerular filtration rate (GFR) is more accurate in detecting chronic kidney disease than serum creatinine estimated GFR [136, 137]. There are no high level evidence publications available which show the optimal management to preserve renal function in these patients [138].

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3.4

Disease management

3.4.1 Introduction The primary aims for treatment of neuro-urological symptoms, and their priorities, are [139, 140]: • protection of the UUT; • achievement (or maintenance) of urinary continence; • restoration of LUT function; • improvement of the patient’s QoL. Further considerations are the patient’s disability, cost-effectiveness, technical complexity and possible complications [140]. Renal failure is the main mortality factor in SCI patients who survive the trauma [141, 142]. Keeping the detrusor pressure during both the filling and voiding phases within safe limits significantly reduces the mortality from urological causes in these patients [143-145] and has consequently become the top priority in the treatment of patients with neuro-urological symptoms [139, 140]. In patients with high detrusor pressure during the filling phase (DO, low bladder compliance), treatment is aimed primarily at conversion of an overactive, high-pressure bladder into a low-pressure reservoir despite the resulting residual urine [139]. Reduction of the detrusor pressure contributes to urinary continence, and consequently to social rehabilitation and QoL. It is also pivotal in preventing UTIs [146, 147]. However, complete continence cannot always be obtained. 3.4.2 Non-invasive conservative treatment 3.4.2.1 Assisted bladder emptying - Credé manoeuvre, Valsalva manoeuvre, triggered reflex voiding Incomplete bladder emptying is a serious risk factor for UTI, high intravesical pressure and incontinence. Methods to improve the voiding process should therefore be practiced. Bladder expression: The downwards movement of the lower abdomen by suprapubic compression (Credé) or by abdominal straining (Valsalva) leads to an increase in intravesical pressure, and generally also causes a reflex sphincter contraction [148, 149]. The latter may increase bladder outlet resistance and lead to inefficient emptying. The high pressures created during these procedures are hazardous for the urinary tract [150, 151]. Therefore, their use should be discouraged unless urodynamics show that the intravesical pressure remains within safe limits [140]. Long-term complications are unavoidable for both methods of bladder emptying [149]. The already weak pelvic floor function may be further impaired, thus introducing or exacerbating already existing stress urinary incontinence [151]. Triggered reflex voiding: Stimulation of the sacral or lumbar dermatomes in patients with a upper motor neuron lesion can elicit a reflex detrusor contraction [151]. The risk of high pressure voiding is present and interventions to decrease outlet resistance may be necessary [152]. Triggering can induce AD, especially in patients with high level SCI (at or above Th 6) [153]. All assisted bladder emptying techniques require low outlet resistance. Even then, high detrusor pressures may still be present. Hence, patients need dedicated education and close urodynamic and urological surveillance [151, 154, 155]. Note: In the literature, including some of the references cited here, the concept “reflex voiding” is sometimes used to cover all three assisted voiding techniques described in this section. External appliances: Social continence may be achieved by collecting urine during incontinence, for instance using pads. Condom catheters with urine collection devices are a practical method for men [140]. The penile clamp is absolutely contraindicated in case of NDO or low bladder compliance because of the risk of developing high intravesical pressure and pressure sores/necrosis in cases of altered/absent sensations. 3.4.2.2 Neuro-urological rehabilitation 3.4.2.2.1 Bladder rehabilitation including electrical stimulation The term bladder rehabilitation summarises treatment options that aim to re-establish bladder function in patients with neuro-urological symptoms. Strong contraction of the urethral sphincter and/or pelvic floor, as well as anal dilatation, manipulation of the genital region, and physical activity inhibit micturition in a reflex manner [140, 156]. The first mechanism is affected by activation of efferent nerve fibres, and the latter ones are produced by activation of afferent fibres [116]. Electrical stimulation of the pudendal nerve afferents strongly inhibits the micturition reflex and detrusor contraction [157]. This stimulation might then support the restoration of the balance between excitatory and inhibitory inputs at the spinal or supraspinal level [140, 158]. Evidence

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for bladder rehabilitation using electrical stimulation in neurological patients is mainly based on small noncomparative studies with high risk of bias. Peripheral temporary electrostimulation: Tibial nerve stimulation and transcutaneous electrical nerve stimulation (TENS) might be effective and safe for treating neurogenic LUT dysfunction, but more reliable evidence from well-designed randomised controlled trials (RCTs) is required to reach definitive conclusions [158-160]. In poststroke patients TENS has been shown to effectively improve urodynamic findings and QoL [161-163]. Peripheral temporary electrostimulation combined with pelvic floor muscle training and biofeedback: In MS patients, combining active neuromuscular electrical stimulation with pelvic floor muscle training and EMG biofeedback can achieve a substantial reduction of neuro-urological symptoms [164, 165]. This treatment combination seems to be more effective than either therapy alone [166, 167]. However, the combination of intravaginal electrostimulation and pelvic floor muscle training was not superior to pelvic floor muscle training alone in reducing urinary incontinence in women with incomplete spinal cord injury [168]. Intravesical electrostimulation: Intravesical electrostimulation can increase bladder capacity and improve bladder filling sensation in patients with incomplete SCI or myelomeningocele (MMC) [169]. In patients with neurogenic detrusor underactivity, intravesical electrostimulation may also improve voiding and reduce residual volume [170, 171]. Repetitive transcranial magnetic stimulation: Although improvement of neuro-urological symptoms has been described in PD and MS patients, this technique is still under investigation [172, 173]. Summary: To date, bladder rehabilitation techniques are mainly based on electrical or magnetic stimulation; however, there is a lack of well-designed studies. 3.4.2.3 Drug treatment A single, optimal, medical therapy for neuro-urological symptoms is not always available. Commonly, a combination of different therapies (e.g. intermittent catheterisation and antimuscarinic drugs) is advised to prevent urinary tract damage and improve long-term outcomes, particularly in patients with a suprasacral SCI or MS [151, 174-176]. 3.4.2.3.1 Drugs for storage symptoms Antimuscarinic drugs: Are the first-line choice for treating NDO, increasing bladder capacity and reducing episodes of UI secondary to NDO by the inhibition of parasympathetic pathways [140, 177-183]. Antimuscarinic drugs have been used for many years to treat patients with NDO [181, 182, 184], and the responses of individual patients to antimuscarinic treatment are variable. Despite a meta-analysis confirming the clinical and urodynamic efficacy of antimuscarinic therapy compared to placebo in adult NDO, a more recent integrative review has indicated that the information provided is still too limited for clinicians to be able to match trial data to the needs of individual patients with SCI, mainly due to the lack of use of standardised clinical evaluation tools such as the American Spinal Injury Association bladder diary and validated symptoms score [182, 185]. Higher doses or a combination of antimuscarinic agents may be an option to maximise outcomes in neurological patients [178, 179, 186-189]. However, these drugs have a high incidence of adverse events, which may lead to early discontinuation of therapy. Despite this, NDO patients have generally shown better treatment adherence compared to idiopathic DO patients [190]. Choice of antimuscarinic agent: Oxybutynin [140, 178, 179, 181, 182, 191], trospium [182, 188, 192], tolterodine [193] and propiverine [182, 194] are established, effective and well tolerated treatments even in long-term use [181, 182, 195, 196]. Darifenacin [197, 198] and solifenacin [199] have been evaluated in NDO secondary to SCI and MS [182, 197-199] with results similar to other antimuscarinic drugs. A pilot study using solifenacin in NDO due to PD showed an improvement in UI [200]. Fesoterodine, an active metabolite of tolterodine, has also been introduced; to date there has been no published clinical evidence for its use in the treatment of neurourological disorders. Favourable results with the new drug imidafenacin have been reported in suprapontine as well as SCI patients [201, 202]. Side effects: Controlled-release antimuscarinics have some minor side effects, e.g. dry mouth [203]. It has been suggested that different ways of administration may help to reduce side effects [204]. Imidafenacine has been safely used in neurological patients with no worsening of cognitive function [201].

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Beta-3-adrenergic receptor agonists The role of mirabegron in neuro-urological patients is still unclear. In MS and SCI patients, with very short follow up, mirabegron has not demonstrated any significant effect on detrusor pressure or cystometric capacity despite the reported improvement in LUTS [205, 206]. A significant subjective improvement in OAB symptoms has also been reported using lower dosages of mirabegron in patients affected by CNS lesions without any negative effects on voiding function [207]. A standard dosage of 50 mg has been found effective with no worsening of cognitive function in patients with PD [208]. Combination therapy with mirabegron and desmopressin in MS patients has shown promising results; however, clinical experience is still very limited in neuro-urological populations [209]. Other drugs In preliminary studies, improvements in daily incontinence rates, nocturia, daytime and 24 hour voids, as well as the low risk of adverse events, suggest that cannabinoids may be effective and safe in MS patients [210]. A concomitant improvement in OAB symptoms has been reported in male MS patients using daily tadalafil to treat neurogenic erectile dysfunction (ED) [211]. A systematic review found that desmopressin may be effective for treating nocturia in MS patients; however, adverse events were common, with the included studies being heterogeneous and of low quality [212]. 3.4.2.3.2 Drugs for voiding symptoms Detrusor underactivity: Cholinergic drugs, such as bethanechol and distigmine, have been considered to enhance detrusor contractility and promote bladder emptying, but are not frequently used in clinical practice [213]. Only preclinical studies have documented the potential benefits of cannabinoid agonists for improving detrusor contractility when administered intravesically [214, 215]. Decreasing bladder outlet resistance: α-blockers (e.g. tamsulosin, naftopidil and silodosin) seem to be effective for decreasing bladder outlet resistance, PVR and AD [216-218]. Increasing bladder outlet resistance: Several drugs have shown efficacy in selected cases of mild SUI, but there are no high-level evidence studies in neurological patients [140]. 3.4.2.4

Summary of evidence and recommendations for drug treatments

Summary of evidence Long-term efficacy and safety of antimuscarinic therapy for NDO is well documented. Mirabegron does not improve urodynamic outcomes in NDO patients. Maximise outcomes for neurogenic detrusor overactivity by considering a combination therapy.

Recommendations Use antimuscarinic therapy as the first-line medical treatment for neurogenic detrusor overactivity. Prescribe α-blockers to decrease bladder outlet resistance. Do not prescribe parasympathomimetics for underactive detrusor.

LE 1a 1b 3

Strength rating Strong Strong Strong

3.4.2.5 Minimally invasive treatment 3.4.2.5.1 Catheterisation Intermittent self- or third-party catheterisation [219, 220] is the preferred management for neuro-urological patients who cannot effectively empty their bladders [140]. Sterile IC, as originally proposed by Guttmann and Frankel [219], significantly reduces the risk of UTI and bacteriuria [140, 221, 222], compared with clean IC introduced by Lapides et al. [220]. However, it has not yet been established whether or not the incidence of UTI, other complications and user satisfaction are affected by either sterile or clean IC, coated or uncoated catheters or by any other strategy [223]. Sterile IC cannot be considered a routine procedure [140, 222]. Aseptic IC is an alternative to sterile IC [224]. The use of hydrophilic catheters was associated with a lower rate of UTI [225]. Contributing factors to contamination are insufficient patient education and the inherently greater risk of UTI in neuro-urological patients [140, 226-230]. The average frequency of catheterisations per day is four to six times [231] and the catheter size most often used is between 12-16 Fr. In aseptic IC, an optimum frequency of five

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times showed a reduction of UTI [231]. Ideally, bladder volume at catheterisation should, as a rule, not exceed 400-500 mL. Indwelling transurethral catheterisation and, to a lesser extent, suprapubic cystostomy are associated with a range of complications as well as an enhanced risk for UTI [140, 232-239]; therefore, both procedures should be avoided, when possible. Silicone catheters are preferred as they are less susceptible to encrustation and because of the high incidence of latex allergy in the neuro-urological patient population [240]. 3.4.2.5.2 Summary of evidence and recommendations for catheterisation Summary of evidence Intermittent catheterisation is the standard treatment for patients who are unable to empty their bladder. Indwelling transurethral catheterisation and suprapubic cystostomy are associated with a range of complications as well as an enhanced risk for UTI.

Recommendations Use intermittent catheterisation, whenever possible aseptic technique, as a standard treatment for patients who are unable to empty their bladder. Thoroughly instruct patients in the technique and risks of intermittent catheterisation. Avoid indwelling transurethral and suprapubic catheterisation whenever possible.

LE 3 3

Strength rating Strong Strong Strong

3.4.2.5.3 Intravesical drug treatment To reduce DO, antimuscarinics can also be administered intravesically [204, 241-244]. The efficacy, safety and tolerability of intravesical administration of 0.1% oxybutynin hydrochloride compared to its oral administration for treatment of NDO has been demonstrated in a recent randomised controlled study [204]. This approach may reduce adverse effects due to the fact that the antimuscarinic drug is metabolised differently [241] and a greater amount is sequestered in the bladder, even more than with electromotive administration [242]. The vanilloids, capsaicin and resiniferatoxin, desensitise the C-fibres for a period of a few months [245, 246]. Clinical studies have shown that resiniferatoxin has limited clinical efficacy compared to botulinum toxin A injections in the detrusor [245]. Although preliminary data suggest that intravesical vanilloids might be effective for treating neurogenic LUT dysfunction, their safety profile appears to be unfavourable [247]. Currently, there is no indication for the use of these substances, which are not licensed for intravesical treatment. 3.4.2.5.4 Summary of evidence and recommendations for intravesical drug treatment Summary of evidence A significant reduction in adverse events was observed for intravesical administration of oxybutynine compared to oral administration.

Recommendation Offer intravesical oxybutynin to neurogenic detrusor overactivity patients with poor tolerance to the oral route.

LE 1a

Strength rating Strong

3.4.2.5.5 Botulinum toxin injections in the bladder Botulinum toxin A causes a long-lasting but reversible chemical denervation that lasts for about nine months [248, 249]. The toxin injections are mapped over the detrusor in a dosage that depends on the preparation used. Botulinum toxin A has been proven effective in patients with neuro-urological disorders due to MS, SCI and PD in multiple RCTs and meta-analyses [250-252]. Urodynamic studies might be necessary after treatment in patients with maximal filling pressure of > 40 cm H2O cm in order to monitor the effect of the injections on bladder pressure [253]. Repeated injections seem to be possible without loss of efficacy, even after initial low response rates, based on years of follow up [248, 254-257]. The clinical efficacy of botulinum toxin A injection in patients with low morbidity after failure of augmentation enterocystoplasty has been demonstrated [258]. A switch between different toxin variations may improve responsiveness [259]. The most frequent side

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effects are UTIs, urinary retention and haematuria [260]. Intermittent catheterisation may become necessary, this is especially relevant in MS patients as they do not often perform IC prior to intravesical botulinum toxin injections. However, a lower dose of botulinum toxin A (100 U) may reduce the rate of clean IC in MS patients [261]. Rare complications include generalised muscle weakness and AD [260]. Current research focuses on different delivery approaches to injection such as liposome encapsulated botulinum toxin to decrease side effects [262]. Neuro-urological patients with an indwelling catheter and concomitant bladder pain and/or catheter bypass leakage could benefit from intravesical botulinum injections [263]. 3.4.2.5.6 Bladder neck and urethral procedures Reduction of the bladder outlet resistance may be necessary to protect the UUT. This can be achieved by chemical denervation of the sphincter or by surgical interventions (bladder neck or sphincter incision or urethral stent – Section 3.4.3.1). Incontinence may result and can be managed by external devices (Section 3.4.2.1). Botulinum toxin A: This can be used to treat DSD effectively by injecting the sphincter at a dose that depends on the preparation used. The dyssynergia is abolished only for a few months, necessitating repeat injections. The efficacy of this treatment has been reported to be high with few adverse effects [264-266]. However, a recent Cochrane report concluded that, because of limited evidence, future RCTs assessing the effectiveness of botulinum toxin A injections also need to address the uncertainty about the optimal dose and mode of injection [267]. In addition, this therapy is not licensed. Balloon dilatation: Favourable immediate results were reported [268], but there have been no further reports since 1994; therefore, this method is no longer recommended. Increasing bladder outlet resistance: This can improve the continence condition. Despite early positive results with urethral bulking agents, a relative early loss of continence is reported in patients with neuro-urological disorders [140, 269, 270]. Urethral inserts: Urethral plugs or valves for the management of (female) stress incontinence have not been applied in neuro-urological patients. The experience with active pumping urethral prosthesis for treatment of the underactive or acontractile detrusor were disappointing [271]. 3.4.2.5.7 S  ummary of evidence and recommendations for botulinum toxin A injections and bladder neck procedures Summary of evidence Botulinum toxin A has been proven effective in patients with neuro-urological disorders due to MS or SCI in multiple RCTs and meta-analyses. Bladder neck incision is indicated only for secondary changes (fibrosis) at the bladder neck.

Recommendations Use botulinum toxin injection in the detrusor to reduce neurogenic detrusor overactivity in multiple sclerosis or spinal cord injury patients if antimuscarinic therapy is ineffective. Bladder neck incision is effective in a fibrotic bladder neck.

LE 1a 4

Strength rating Strong Strong

3.4.3 Surgical treatment There is considerable heterogeneity in outcome parameters and definitions of cure used to report on outcome of surgical interventions for SUI in neuro-urological patients [272]. The heterogeneity of outcome reporting makes it difficult to interpret and compare different studies and therapies. A consistent comparison of the outcomes of therapy can only be made after standardisation of outcome parameters and definitions of cure or success; therefore, it would seem prudent to develop a core outcome set (COS) for use in UI research in neuro-urological patients [272]. Until such a COS is developed it would seem feasible to use both a subjective and objective outcome parameter and the combination of both to define cure [272]. Due to the importance of QoL for neuro-urological patients a disease-specific QoL questionnaire or a bother questionnaire validated for neuro-urological patients should be used as the subjective outcome parameter [272]. 3.4.3.1 Bladder neck and urethral procedures Increasing the bladder outlet resistance has the inherent risk of causing high intravesical pressure. Procedures to treat sphincteric incontinence are therefore suitable only when the detrusor activity can be controlled and when no significant reflux is present. A simultaneous bladder augmentation and IC may be necessary [140]. NEURO-UROLOGY - LIMITED UPDATE MARCH 2020

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Urethral sling: Various materials have been used for this procedure with enduring positive results. The procedure is established in women with the ability to self-catheterise [140, 273-276]. There is growing evidence that synthetic slings can be used effectively with acceptable medium to long-term results and minimal morbidity in neurological patients [277, 278]. Besides the pubovaginal sling, which has been considered the procedure of choice in this subgroup of patients, recent reports suggest that both the transobturator and the retropubic approaches may also be considered, with similar failure rates and a reduction in the need for IC. However, for both approaches a higher incidence of de novo urgency was reported [278, 279]. In men, both autologous and synthetic slings may also be an alternative [280-284]. Artificial urinary sphincter (AUS): This device was introduced by Light and Scott for patients with neurourological disorders [285]. It has stood the test of time and acceptable long-term outcomes can be obtained [286]. However, the complication rates and re-operation rates are higher than in non-neurogenic patient groups (up to 60%), so it is advisable that patients are conscientiously informed about the success rates as well as the complications that may occur after the procedure [287, 288]. In a case series with 25 years follow up only 7.1% of patients were revision free at 20 years [289]. Re-interventions are commonly due to infection, urethral atrophy or erosion and mechanical failure. There is growing interest in the use of this device in women with development of laparoscopic and robotassisted approaches which appear to reduce infection and erosion rates [290-293]. Long-term surgical and patient-reported outcomes are needed to determine the role of AUS placement in female patients with neurogenic SUI [294]. Adjustable continence device - ProACT/ACT®: The efficacy of this device has been reported mainly in postprostatectomy incontinence. A marginally lower cure rate has been reported in neurological patients when compared to non-neurological patients [295]. A retrospective study in neuro-urological patients reported a low rate of efficacy and high complication rate for this device [296]. Functional sphincter augmentation: Transposing the gracilis muscle to the bladder neck [297] or proximal urethra [298], can enable the possible creation of a functional autologous sphincter by electrical stimulation [297-299]; therefore, raising the prospect of restoring control over the urethral closure. Bladder neck and urethra reconstruction: The classical Young-Dees-Leadbetter procedure [300] for bladder neck reconstruction in children with bladder exstrophy, and Kropp urethra lengthening [301] improved by Salle [302], are established methods to restore continence provided that IC is practiced and/or bladder augmentation is performed [140, 303]. Endoscopic techniques for treating anatomic bladder outlet obstruction [304]: • Transurethral resection of the prostate is indicated in male patients with refractory LUT symptoms due to benign prostatic obstruction. Special consideration should be given to pre-operative abnormal sphincter function which can lead to de novo or persistent UI [305, 306]. • Bladder neck resection is indicated in patients with high PVR and when a prominent obstruction of the sclerotic ring in the bladder neck is identified during cystoscopy. The resection can be performed between the three or nine o’clock position or full circle [307]. • Urethrotomy is indicated in patients with urethral strictures. Cold knife or neodymium:YAG contact laser urethrotomy at the twelve o’clock position can be performed [308, 309]. In recurrent strictures, open surgery should be considered. • Sphincterotomy has been shown to be an efficient technique for the resolution of AD, hydronephrosis and recurrent UTI, and for decreasing detrusor pressures, PVR and vesicoureteral reflux. It is irreversible and should be limited to men who are able to wear a condom catheter. By staged incision, bladder outlet resistance can be reduced without completely losing the closure function of the urethra [139, 140, 310]. The incision with less complications is the twelve o’clock sphincterotomy with cold knife [311] or neodymium:YAG laser [312]. Sphincterotomy needs to be repeated at regular intervals in many patients [313], but it is efficient and does not cause severe adverse effects [139, 268]. Secondary narrowing of the bladder neck may occur, for which combined bladder neck incision might be considered [314]. Bladder neck incision: This is indicated only for secondary changes at the bladder neck (fibrosis) [139, 315]. This procedure is not recommended in patients with detrusor hypertrophy, which causes thickening of the bladder neck [139].

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Stents: Implantation of urethral stents results in continence being dependent on adequate closure of the bladder neck [140]. The results are comparable with sphincterotomy and the stenting procedure has a shorter duration of surgery and hospital stay [316, 317]. However, the costs [139], possible complications and re-interventions [318, 319] are limiting factors in their use [320-323]. 3.4.3.2 Denervation, deafferentation, sacral neuromodulation Sacral anterior root stimulation (SARS) is aimed at producing detrusor contraction. The technique was developed by Brindley [324] and is only applicable to complete lesions above the implant location, as its stimulation amplitude is over the pain threshold. The urethral sphincter efferents are also stimulated, but because the striated muscle relaxes faster than the smooth muscle of the detrusor, so-called “post-stimulus voiding” occurs. This approach has been successful in highly selected patients [325-327]. Although it has been shown that detrusor pressure during SARS decreases over time, the changes do not seem to be clinically relevant during the first decade after surgery [328]. By changing the stimulation parameters, this method can also induce defecation or erection. A recent study reported that Charcot spinal arthropathy should be considered as a potential long-term complication of SARS, leading to spinal instability and to SARS dysfunction [329]. Sacral rhizotomy, also known as sacral deafferentation, has achieved some success in reducing DO [330-332], but nowadays, it is used mostly as an adjuvant to SARS [325, 333-336]. Alternatives to rhizotomy are sought in this treatment combination [337-339]. Sacral neuromodulation [340] might be effective and safe for treating neuro-urological symptoms, but there is a lack of RCTs and it is unclear which neurological patients are most suitable [341-344]. 3.4.3.3 Bladder covering by striated muscle When the bladder is covered by striated muscle, that can be stimulated electrically, or ideally that can be contracted voluntarily, voiding function can be restored to an acontractile bladder. The rectus abdominis [345] and latissimus dorsi [346] have been used successfully in patients with neuro-urological symptoms [347, 348]. 3.4.3.4 Bladder augmentation The aim of auto-augmentation (detrusor myectomy) is to reduce DO or improve low bladder compliance. The advantages are: low surgical burden, low rate of long-term adverse effects, positive effect on patient QoL, and it does not preclude further interventions [139, 140, 349-352]. Replacing or expanding the bladder by intestine or other passive expandable coverage will improve bladder compliance and at least reduce the pressure effect of DO [353, 354]. Improved QoL and stable renal function has been reported during long-term follow-up [355]. Patients performing IC with augmentation cystoplasty had better urinary function and satisfaction with their urinary symptoms compared to patients performing IC with or without botulinum toxin treatment [356]. Long-term complications included bladder perforation (1.9%), mucus production (12.5%), metabolic abnormalities (3.35%), bowel dysfunction (15%), and stone formation (10%) [355]. The procedure should be used with caution in patients with neuro-urological symptoms, but may become necessary if all less-invasive treatment methods have failed. Special attention should be paid to patients with pre-operative renal scars since metabolic acidosis can develop [357]. Bladder substitution with bowel after performing a supratrigonal cystectomy [354], to create a low-pressure reservoir, is indicated in patients with a severely thick and fibrotic bladder wall [140]. Intermittent catheterisation may become necessary after this procedure. The long-term scientific evidence shows that bladder augmentation is a highly successful procedure that stabilises renal function and prevents anatomical deterioration; however, lifelong follow-up is essential in this patient group given the significant morbidity associated with this procedure [355, 358]. 3.4.3.5 Urinary diversion When no other therapy is successful, urinary diversion must be considered for the protection of the UUT and for the patient’s QoL [140]. Continent diversion: This should be the first choice for urinary diversion. Patients with limited dexterity may prefer a stoma instead of using the urethra for catheterisation. For cosmetic reasons, the umbilicus is often used for the stoma site [359-364]. A systematic review of the literature concluded that continent catheterisable tubes/stomas are an effective treatment option in neuro-urological patients unable to perform intermittent selfcatheterisation through the urethra [365]. However, the complication rates were significant with 85/213 postoperative events requiring re-operation [365]. Tube stenosis occurred in 4-32% of the cases. Complications related to concomitant procedures (augmentation cystoplasty, pouch) included neovesicocutaneous fistulae (3.4%), bladder stones (20-25%), and bladder perforations (40%). In addition, data comparing HRQoL before and after surgery were not reported [365]. NEURO-UROLOGY - LIMITED UPDATE MARCH 2020

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Incontinent diversion: If catheterisation is impossible, incontinent diversion with a urine-collecting device is indicated. Ultimately, it could be considered in patients who are wheelchair bound or bed-ridden with intractable and untreatable incontinence, in patients with LUT destruction, when the UUT is severely compromised, and in patients who refuse other therapy [140]. An ileal segment is used for the deviation in most cases [140, 366-369]. Patients gain better functional status and QoL after surgery [370]. Undiversion: Long-standing diversions may be successfully undiverted or an incontinent diversion changed to a continent one with the emergence of new and better techniques for control of detrusor pressure and incontinence [140]. The patient must be carefully counselled and must comply meticulously with the instructions [140]. Successful undiversion can then be performed [371]. 3.4.3.6

Summary of evidence and recommendations for surgical treatment

Summary of evidence Bladder augmentation is an effective option to decrease detrusor pressure and increase bladder capacity, when all less-invasive treatment methods have failed. Urethral sling placement is an established procedure, with acceptable medium- to long-term results, in women with the ability to self-catheterise. Artificial urinary sphincter insertion is a viable option, with acceptable long-term outcomes, in males. The complication and re-operation rates are higher in neuro-urological patients; therefore, patients must be adequately informed regarding the success rates as well as the complications that may occur following the procedure.

Recommendations Perform bladder augmentation in order to treat refractory neurogenic detrusor overactivity. Place an autologous urethral sling in female patients with neurogenic stress urinary incontinence who are able to self-catheterise. Insert an artificial urinary sphincter in male patients with neurogenic stress urinary incontinence.

3.5

LE 3 3 3

Strength rating Strong Strong Strong

Urinary tract infection in neuro-urological patients

3.5.1 Epidemiology, aetiology and pathophysiology Urinary tract infection is the onset of signs and/or symptoms accompanied by laboratory findings of a UTI (bacteriuria, leukocyturia and positive urine culture) [360]. There are no evidence-based cut-off values for the quantification of these findings. The published consensus is that a significant bacteriuria in persons performing IC is present with > 102 cfu/mL, > 104 cfu/mL in clean-void specimens and any detectable concentration in suprapubic aspirates. Regarding leukocyturia, ten or more leukocytes in centrifuged urine samples per microscopic field (400x) are regarded as significant [360]. The pathogenesis of UTI in neuro-urological patients is multifactorial. Male gender seems to be a risk factor for febrile UTI [372]. Several etiological factors have been described: altered intrinsic defence mechanisms, impaired washout and catheterisation [373]. Poor glycemic control has been established as a risk factor for UTI in women with type 1 diabetes [374]. However, the exact working mechanisms remain unknown. The presence of asymptomatic bacteriuria in SCI patients is higher than in the general population, and varies depending on bladder management. Prevalence of bacteriuria in those performing clean IC varies from 23-89% [375]. Sphincterotomy and condom catheter drainage has a 57% prevalence [376]. Asymptomatic bacteria should not be routinely screened for in this population [377]. Individuals with neuro-urological symptoms, especially those with SCI, may have other signs and symptoms in addition to or instead of traditional signs and symptoms of a UTI in able-bodied individuals. Other problems, such as AD, may develop or worsen due to a UTI [225]. The most common signs and symptoms suspicious of a UTI in those with neuro-urological disorders are fever, new onset or increase in incontinence, including leaking around an indwelling catheter, increased spasticity, malaise, lethargy or sense of unease, cloudy urine with increased urine odour, discomfort or pain over the kidney or bladder, dysuria, or AD [225, 378]. New incontinence is the most specific symptom, whereas cloudy and foul smelling urine has the highest positive predictive value for UTI diagnosis [379].

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3.5.2 Diagnostic evaluation Urine culture and urinalysis are the optimum tests for the diagnosis of UTI in neuro-urological patients. A dipstick test may be more useful to exclude than to prove UTI [380, 381]. As bacterial strains and resistance patterns in persons with neuro-urological disorders may differ from those of able-bodied patients, microbiologic testing is mandatory [382]. 3.5.3 Disease management Bacteriuria in patients with neuro-urological disorders should not be treated. Treatment of asymptomatic bacteriuria results in significantly more resistant bacterial strains without improving the outcome [383]. Urinary tract infections in persons with neuro-urological disorders are by definition a complicated UTI; therefore, single-dose treatment is not advised. There is no consensus in the literature about the duration of treatment as it depends on the severity of the UTI and the involvement of kidneys and the prostate. Generally, a five to seven day course of antibiotic treatment is advised, which can be extended up to fourteen days according to the extent of the infection [383]. The choice of antibiotic therapy should be based on the results of the microbiologic testing. If immediate treatment is mandatory (e.g. fever, septicaemia, intolerable clinical symptoms, extensive AD), the choice of treatment should be based on local and individual resistance profiles [384]. In patients with afebrile UTI, an initial non-antibiotic treatment may be justified [385, 386]. 3.5.3.1 Recurrent UTI Recurrent UTI in patients with neuro-urological disorders may indicate suboptimal management of the underlying functional problem, e.g. high bladder pressure during storage and voiding, incomplete voiding or bladder stones. The improvement of bladder function, by treating DO by botulinum toxin A injection in the detrusor [387], and the removal of bladder stones or other direct supporting factors, especially indwelling catheters, as early as possible, are mandatory [382]. 3.5.3.2 Prevention If the improvement of bladder function and removal of foreign bodies/stones is not successful, additional UTI prevention strategies should be utilised. In a meta-analysis the use of hydrophilic catheters was associated with a lower rate of UTI [225]. Bladder irrigation has not been proven effective [388]. Various medical approaches have been tested for UTI prophylaxis in patients with neuro-urological disorders. The benefit of cranberry juice or probiotics for the prevention of UTI could not be demonstrated in RCTs [389, 390]. Methenamine hippurate is not effective in individuals with neuro-urological symptoms [391]. There is no sufficient evidence to support the use of L-methionine for urine acidification to prevent recurrent UTI [392]. There is only weak evidence that oral immunotherapy reduces bacteriuria in patients with SCI [393] and that recurrent UTIs are reduced [394]. Low-dose, long-term, antibiotic prophylaxis can reduce UTI frequency, but increases bacterial resistance and is therefore not recommended [383]. Weekly cycling of antibiotic prophylaxis provided long-term positive results, but the results of this trial need to be confirmed in further studies [395]. Another possible future option, the inoculation of apathogenic Escherichia coli strains into the bladder, has provided positive results in initial studies, but because of the paucity of data [396], cannot be recommended as a treatment option. There is initial evidence that homeopathic treatment can decrease UTI frequency [397]. In addition, intravesical gentamycin instillations can reduce UTI frequency without increasing the number of multi-resistant bacteria [398]. In summary, based on the criteria of evidence-based medicine, there is currently no preventive measure for recurrent UTI in patients with neuro-urological disorders that can be recommended without limitations. Therefore, individualised concepts should be taken into consideration, including immunostimulation, phytotherapy and complementary medicine [399]. Prophylaxis in patients with neuro-urological disorders is important to pursue, but since there are no data favouring one approach over another, prophylaxis is essentially a trial and error approach.

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3.5.4

Summary of evidence and recommendations for the treatment of UTI

Summary of evidence Treatment of asymptomatic bacteriuria results in significantly more resistant bacterial strains without improving patient outcome. Low-dose, long-term, antibiotic prophylaxis does not reduce UTI frequency, but increases bacterial resistance. Recurrent UTI in patients with neuro-urological disorders may indicate suboptimal management of the underlying functional problem. Improvement of bladder function as early as possible is mandatory. There is currently no preventive measure for recurrent UTI in patients with neuro-urological disorders that can be recommended without limitations. Recommendations Do not screen for or treat asymptomatic bacteriuria in patients with neuro-urological disorders. Avoid the use of long-term antibiotics for recurrent urinary tract infections (UTIs). In patients with recurrent UTI, optimise treatment of neuro-urological symptoms and remove foreign bodies (e.g. stones, indwelling catheters) from the urinary tract. Individualise UTI prophylaxis in patients with neuro-urological disorders as there is no optimal prophylactic measure available.

3.6

LE 1a 2a 3 3

Strength rating Strong Strong Strong Strong

Sexual function and fertility

These Guidelines specifically focus on sexual dysfunction and infertility in patients with a neurological disease [400, 401]. Non-neurogenic, male sexual dysfunction and infertility are covered in separate EAU Guidelines [402, 403]. In neuro-urological patients sexual problems can be identified at three levels: primary (direct neurological damage), secondary (general physical disabilities) and tertiary (psychosocial and emotional issues) sexual dysfunction [404]. Adopting a systematic approach, such as the PLISSIT model (Permission, Limited Information, Specific Suggestions and Intensive Therapy) [405], provides a framework for counselling and treatment involving a stepwise approach to the management of neurogenic sexual dysfunction. Sexual dysfunction is associated with neurogenic LUT dysfunction in patients with MS [406] and SB [407]. Although various patient reported outcome measures (PROMs) are available to evaluate sexual function, the evidence for good PROMs is limited and studies with high methodological quality are needed [408]. 3.6.1 Erectile dysfunction 3.6.1.1 Phosphodiesterase type 5 inhibitors (PDE5Is) Phosphodiesterase type 5 inhibitors (PDE5Is) are recommended as first-line treatment in neurogenic ED [400, 401]. In SCI patients, tadalafil, vardenafil and sildenafil have all improved retrograde ejaculation and improved erectile function and satisfaction on IIEF-15. Tadalafil 10 mg was shown to be more effective than sildenafil 50 mg. All currently available PDE5Is appear to be effective and safe, although there are no high level evidence studies in neuro-urological patients investigating the efficacy and side effects across different PDE5Is, dosages and formulations [409]. For MS patients two studies reported significant improvement in ED when using sildenafil and tadalafil. One study; however, showed no improvement in ED with sildenafil. In PD normal erectile function was described in over half of the patients using sildenafil 100 mg and a significant improvement in IIEF-15 score was found compared to placebo. While most neuro-urological patients require long-term therapy for ED some have a low compliance rate or stop therapy because of side effects [410, 411], most commonly headache and flushing [401]. In addition, PDE5Is may induce relevant hypotension in patients with tetraplegia/high-level paraplegia and multiple system atrophy [410, 411]. As a prerequisite for successful PDE5I-therapy, some residual nerve function is required to induce erection. Since many patients with SCI use on-demand nitrates for the treatment of AD, they must be counselled that PDE5Is are contraindicated when using nitrate medication. 3.6.1.2 Drug therapy other than PDE5Is Fampridine to treat neurogenic spasticity has been shown to be beneficial in improving ED in two domains of the IIEF-15 in SCI and MS patients, however, with a significant discontinuation rate due to severe adverse

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events [412]. Sublingual apomorfine was shown to have poor results on ED in SCI patients and side-effects in half of the patients [413]. In PD pergolide mesylate showed a significant improvement in IIEF-15 scores up to twelve months follow-up [414]. 3.6.1.3 Mechanical devices Mechanical devices (vacuum tumescence devices and penile rings) may be effective but are less popular [415-419]. 3.6.1.4 Intracavernous injections and intraurethral application Patients not responding to oral drugs may be offered intracavernous injections (alprostadil, papaverine and phentolamine) that have been shown to be effective in a number of neurological conditions, including SCI, MS, and diabetes mellitus [420-426], but their use requires careful dose titration and some precautions. Complications of intracavernous drugs include pain, priapism and corpora cavernosa fibrosis. Intracavernous vasoactive drug injection is the first-line therapeutic option in patients taking nitrate medications, as well as those with concerns about drug interactions with PDE5Is, or in whom PDE5Is are ineffective. The impact of intracavernous injections on ejaculation and orgasmic function, their early use for increasing the recovery rate of a spontaneous erection, and their effectiveness and tolerability in the long-term are unclear [410]. Intra-urethral alprostadil application is an alternative, but a less effective, route of administration [422, 427]. 3.6.1.5 Sacral neuromodulation Sacral neuromodulation for LUT dysfunction may improve sexual function; however, high level evidence studies are lacking. 3.6.1.6 Penile prostheses Penile prostheses may be considered for treatment of neurogenic ED when all conservative treatments have failed. At a mean follow-up of seven years 83.7% of patients with SCI were able to have sexual intercourse [401]. Serious complications, including infection and prosthesis perforation, may occur in about 10% of patients, depending on implant type [428-430]. 3.6.1.7

Summary of evidence and recommendations for erectile dysfunction

Summary of evidence The long-term efficacy and safety of oral PDE5Is for the treatment of ED is well documented. Intracavernous vasoactive drug injections have been shown to be effective in a number of neurological conditions, including SCI and MS; however, their use requires careful dose titration and precautions. Mechanical devices (vacuum tumescence devices and penile rings) may be effective but are less popular. Reserve penile prostheses for selected patients, those in which all conservative treatments have failed, with neurogenic ED. Recommendations Prescribe oral phosphodiesterase type 5 inhibitors as first-line medical treatment in neurogenic erectile dysfunction (ED). Give intracavernous injections of vasoactive drugs (alone or in combination) as second-line medical treatment in neurogenic ED. Offer mechanical devices such as vacuum devices and rings to patients with neurogenic ED.

LE 1b 3 3 4

Strength rating Strong Strong Strong

3.6.2 Male fertility Male fertility can be compromised in the neurological patient by ED, ejaculation disorder, impaired sperm quality or various combinations of these three disorders. Among the major conditions contributing to neurogenic infertility are pelvic and retroperitoneal surgery, diabetes mellitus, SB, MS and SCI [431]. Erectile dysfunction is managed as described previously. Retrograde ejaculation may be reversed by sympathomimetic agents contracting the bladder neck, including imipramine, ephedrine, pseudoephedrine, and phenylpropanolamine [431]. The use of a balloon catheter to obstruct the bladder neck may be effective in obtaining antegrade ejaculation [432]. If antegrade ejaculation is not achieved, the harvest of semen from the urine may be considered [433].

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Prostatic massage is safe and easy to use for obtaining semen in men with lesions above Th 10 [434]. In several patients, vibrostimulation or transrectal electroejaculation are needed for sperm retrieval [431, 435, 436]. Semen retrieval is more likely with vibrostimulation in men with lesions above Th 10 [437-439]. In men with SCI, especially at or above Th 6, AD might occur during sexual activity and ejaculation [440, 441]; patients at risk and fertility clinics must be informed and aware of this potentially life-threatening condition. In SCI patients the use of oral midodrine can improve sperm retrieval at vibrostimulation [442]. In men with MS, use of disease modifying drugs during the conception phase, has not been associated with altered pregnancy outcomes [443]. Surgical procedures, such as, microsurgical epididymal sperm aspiration (MESA) or testicular sperm extraction (TESE), may be used if vibrostimulation and electroejaculation are not successful [444, 445]. Pregnancy rates in patients with SCI are lower than in the general population, but since the introduction of intracytoplasmic sperm injection (ICSI), men with SCI now have a good chance of becoming biological fathers [446-448]. 3.6.2.1 Sperm quality and motility The following has been reported on sperm quality and motility: • bladder management with clean IC may improve semen quality compared to indwelling catheterisation, reflex voiding or bladder expression [449]; • in SCI patients sperm quality decreases at the early post traumatic phase demonstrating lower spermatozoid vitality (necrospermia), reduced motility (asthenospermia) and leucospermia [444]; • long-term valproate treatment for epilepsy negatively influences sperm count and motility [450]; • vibrostimulation produces samples with better sperm motility than electrostimulation [451, 452]; • electroejaculation with interrupted current produces better sperm motility than continuous current [453]; • freezing of sperm is unlikely to improve fertility rates in men with SCI [454]. 3.6.2.2

Summary of evidence and recommendations for male fertility

Summary of evidence Vibrostimulation and transrectal electroejaculation have been shown to be effective for sperm retrieval in neuro-urological patients. Surgical procedures, such as, microsurgical epididymal sperm aspiration or testicular sperm extraction, may be used if vibrostimulation and electroejaculation are not successful. In men with SCI at or above Th 6, AD might occur during sexual activity and ejaculation.

Recommendations Perform vibrostimulation and transrectal electroejaculation for sperm retrieval in men with spinal cord injury. Perform microsurgical epididymal sperm aspiration, testicular sperm extraction and intracytoplasmic sperm injection after failed vibrostimulation and/or transrectal electroejaculation in men with spinal cord injury. Counsel men with spinal cord injury at or above Th 6 and fertility clinics about the potentially life-threatening condition of autonomic dysreflexia.

LE 1b 3 3

Strength rating Strong Strong

Strong

3.6.3 Female sexuality The most relevant publications on neurogenic female sexual dysfunction are in women with SCI and MS. After SCI, about 65-80% of women continue to be sexually active, but to a much lesser extent than before the injury, and about 25% report a decreased satisfaction with their sexual life [455-458]. Although sexual dysfunction is very common in women with MS, it is still often overlooked by medical professionals [459, 460]. The greatest physical barrier to sexual activity is UI. A correlation has been found between the urodynamic outcomes of low bladder capacity, compliance and high maximum detrusor pressure and sexual dysfunction in MS patients. Problems with positioning and spasticity affect mainly tetraplegic patients. Peer support may help to optimise the sexual adjustment of women with SCI in achieving a more positive selfimage, self-esteem and feelings of being attractive to themselves and others [455, 461-463]. The use of specific drugs for sexual dysfunction is indicated to treat inadequate lubrication. Data on sildenafil for treating female sexual dysfunction are poor and controversial [401]. Although good evidence exists that psychological interventions are effective in the treatment of female hypoactive sexual desire disorder and female orgasmic disorder [464], there is a lack of high-level evidence studies in the neurological population.

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Neurophysiological studies have shown that women with the ability to perceive Th 11-L2 pin-prick sensations may have psychogenic genital vasocongestion. Reflex lubrication and orgasm is more prevalent in women with SCI who have preserved the sacral reflex arc (S2-S5), even when it has not been shown in an individual woman that a specific level and degree of lesion is the cause of a particular sexual dysfunction. In SCI women with a complete lesion of the sacral reflex, arousal and orgasm may be evoked through stimulation of other erogenous zones above the level of lesions [465-467]. Sacral neuromodulation for LUT dysfunction may improve sexual function but high-evidence studies are lacking [401]. Women with SCI reported dissatisfaction with the quality and quantity of sexuality-related rehabilitation services and were less likely to receive sexual information than men [465, 468, 469]. 3.6.4 Female fertility There are few studies on female fertility in neurological patients. More than a third (38%) of women with epilepsy had infertility and the relevant predictors were exposure to multiple (three or more) antiepileptic drugs, older age and lower education [470]. Although it seems that the reproductive capacity of women with SCI is only temporarily affected by SCI with cessation of menstruation for approximately six months after SCI [471], there are no high-level evidence studies. About 70% of sexually active women use some form of contraception after injury, but fewer women use the birth control pill compared to before their injury [472]. Women with SCI are more likely to suffer complications during pregnancy, labour and delivery compared to able-bodied women. Complications of labour and delivery include bladder problems, spasticity, pressure sores, anaemia, and AD [473-477]. Obstetric outcomes include higher rates of Caesarean sections and an increased incidence of low birth-weight babies [472, 475-477]. Epidural anaesthesia is chosen and effective for most patients with AD during labour and delivery [478, 479]. There is very little published data on women’s experience of the menopause following SCI [480]. Women with MS who plan a pregnancy should evaluate their current drug treatment with their treating physician [481-483]. Clinical management should be individualised to optimise both the mother’s reproductive outcomes and MS course [482-484]. 3.6.4.1

Summary of evidence and recommendation for female sexuality and fertility

Summary of evidence Data on specific drugs for treating female sexual dysfunction are poor and controversial. There are limited numbers of studies on female fertility in neurological patients, clinical management should be individualised to optimise both the mother’s reproductive outcomes and medical condition.

Recommendations Do not offer medical therapy for the treatment of neurogenic sexual dysfunction in women. Take a multidisciplinary approach, tailored to individual patient’s needs and preferences, in the management of fertility, pregnancy and delivery in women with neurological diseases.

3.7

LE 4 4

Strength rating Strong Strong

Follow-up

3.7.1 Introduction Neuro-urological disorders are often unstable and the symptoms may vary considerably, even within a relatively short period. Regular follow-up is therefore necessary to assess the UUT [138]. Depending on the type of the underlying neurological pathology and the current stability of the neuro-urological symptoms, the interval between initial investigations and control diagnostics may vary and in many cases should not exceed one to two years. In high-risk neuro-urological patients this interval should be much shorter. Urinalysis should be performed only when patients present with symptoms [485]. The UUT should be checked by ultrasonography at regular intervals in high-risk patients; about once every six months [6, 486]. In these patients, physical examination and urine laboratory should take place every year [6, 486]. In MS patients higher scores on the Expanded Disability Status Scale (EDSS) are associated with risk factors for UUT deterioration [53]. A urodynamic investigation should be performed as a diagnostic baseline, and repeated during followup, more frequently in high-risk patients [6, 486]. In addition, bladder wall thickness can be measured on

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ultrasonography as an additional risk assessment for upper tract damage [487], although a ‘safe’ cut-off threshold for this has not been agreed [488]. The utility of DMSA for follow-up of neuro-urological patients has not been fully evaluated [489]. Any significant clinical change warrants further, specialised, investigation [6, 486]. However, there is a lack of high level evidence studies on this topic and every recommendation must be viewed critically in each individual neuro-urological patient [138]. The increased prevalence of muscle invasive bladder cancer in neuro-urological patients also warrants longterm follow-up [490]. The exact frequency of cystoscopy with or without cytology remains unknown, but presence of risk factors similar to the general population should trigger further investigation [485]. Adolescent patients with neurological pathology are at risk of being lost to follow-up during the transition to adulthood. It is important that a standardised approach during this transition is adopted to improve follow-up and specific treatment during adult life [491]. 3.7.2

Summary of evidence and recommendations for follow-up

Summary of evidence Neuro-urological disorders are often unstable and the symptoms may vary considerably, therefore, regular follow-up is necessary.

Recommendations Assess the upper urinary tract at regular intervals in high-risk patients. Perform a physical examination and urine laboratory every year in high-risk patients. Any significant clinical changes should instigate further, specialised, investigation. Perform urodynamic investigation as a mandatory baseline diagnostic intervention in highrisk patients at regular intervals.

3.8

LE 4

Strength rating Strong Strong Strong Strong

Conclusions

Neuro-urological disorders have a multi-faceted pathology. They require an extensive and specific diagnosis before one can embark on an individualised therapy, which takes into account the medical and physical condition of the patient and the patient’s expectations about their future. The urologist can select from a wealth of therapeutic options, each with its own pros and cons. Notwithstanding the success of any therapy embarked upon, close surveillance is necessary for the patient’s entire life. These Guidelines offer you expert advice on how to define the patient’s neuro-urological symptoms as precisely as possible and how to select, together with the patient, the appropriate therapy. This last choice, as always, is governed by the golden rule: as effective as needed, as non-invasive as possible.

4.

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5.

CONFLICT OF INTEREST

All members of the Neuro-urology working group have provided disclosure statements of all relationships that they have that might be perceived as a potential source of a conflict of interest. This information is publically accessible through the European Association of Urology website: http://uroweb.org/guideline. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative and travel and meeting expenses. No honoraria or other reimbursements have been provided.

6.

CITATION INFORMATION

The format in which to cite the EAU Guidelines will vary depending on the style guide of the journal in which the citation appears. Accordingly, the number of authors or whether, for instance, to include the publisher, location, or an ISBN number may vary. The compilation of the complete Guidelines should be referenced as: EAU Guidelines. Edn. presented at the EAU Annual Congress Amsterdam 2020. ISBN 978-94-92671-07-3. If a publisher and/or location is required, include: EAU Guidelines Office, Arnhem, The Netherlands. http://uroweb.org/guidelines/compilations-of-all-guidelines/ References to individual guidelines should be structured in the following way: Contributors’ names. Title of resource. Publication type. ISBN. Publisher and publisher location, year.

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EAU Guidelines on Management of Non-Neurogenic Female Lower Urinary Tract Symptoms (LUTS) C.K. Harding (Chair), M.C. Lapitan (Vice-chair), S. Arlandis, K. Bø, E. Costantini, J. Groen, A.K. Nambiar, M.I. Omar, V. Phé, C.H. van der Vaart Guidelines Associates: F. Farag, M. Karavitakis, M. Manso, S. Monagas, A. Nic an Riogh, E. O’Connor, B. Peyronnet, V. Sakalis, N. Sihra, L. Tzelves

© European Association of Urology 2021

TABLE OF CONTENTS

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1. INTRODUCTION 1.1 Aim and objectives 1.2 Panel composition 1.3 Available publications 1.4 Publication history

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2. METHODS 2.1 Introduction 2.2 Review 2.3 Future goals

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3. DIAGNOSTIS 3.1 History and physical examination 3.1.1 Summary of evidence and recommendation for history taking and physical examination 3.2 Patient questionnaires 3.2.1 Summary of evidence and recommendations for patient questionnaires 3.3 Bladder diaries 3.3.1 Summary of evidence and recommendations for bladder diaries 3.4 Urinalysis and urinary tract infection 3.4.1 Summary of evidence and recommendations for urinalysis 3.5 Post-void residual volume 3.5.1 Summary of evidence and recommendations for post-void residual 3.6 Urodynamics 3.6.1 Variability 3.6.2 Diagnostic accuracy 3.6.3 Predictive value 3.6.4 Summary of evidence and recommendations for urodynamics 3.7 Pad testing 3.7.1 Summary of evidence and recommendations for pad testing 3.8 Imaging 3.8.1 Ultrasound 3.8.2 Detrusor wall thickness 3.8.3 MRI 3.8.4 Summary of evidence and recommendations for imaging

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4. DISEASE MANAGEMENT 4.1 Overactive bladder 4.1.1 Epidemiology, aetiology, pathophysiology 4.1.2 Classification 4.1.3 Diagnostic evaluation 4.1.3.1 Bladder diaries 4.1.3.2 Urodynamics 4.1.3.3 Summary of evidence and recommendations regarding associated conditions 4.1.4 Disease management 4.1.4.1 Conservative management 4.1.4.1.1 Addressing underlying disease/cognitive impairment 4.1.4.1.1.1 Summary of evidence and recommendation regarding associated conditions 4.1.4.1.2 Adjustment of other medication 4.1.4.1.2.1 Summary of evidence and recommendations for adjustment of non-LUTS medication 4.1.4.1.3 Urinary containment 4.1.4.1.3.1 Summary of evidence and recommendations for urinary containment 4.1.4.1.4 Lifestyle interventions

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4.1.4.1.4.1 Caffeine intake 4.1.4.1.4.2 Fluid intake 4.1.4.1.4.3 Obesity and weight loss 4.1.4.1.4.4 Smoking 4.1.4.1.4.5 Summary of evidence and recommendations for lifestyle interventions 4.1.4.1.5 Behavioural and physical therapies 4.1.4.1.5.1 Prompted voiding and timed voiding 4.1.4.1.5.2 Bladder Training 4.1.4.1.5.3 Pelvic floor muscle training 4.1.4.1.5.4 Electrical stimulation 4.1.4.1.5.5 Acupuncture 4.1.4.1.5.6 Posterior tibial nerve stimulation 4.1.4.1.5.6.1 Percutaneous posterior tibial nerve stimulation 4.1.4.1.5.6.2 Transcutaneous posterior tibial nerve stimulation 4.1.4.1.5.7 Summary of evidence and recommendations for behavioural and physical therapies 4.1.4.2 Pharmacological management 4.1.4.2.1 Anticholinergic drugs 4.1.4.2.1.1 Comparison of different anticholinergic agents 4.1.4.2.1.2 Anticholinergic drugs vs. conservative treatment 4.1.4.2.1.3 Anticholinergic drugs: adherence and persistence 4.1.4.2.1.4 Summary of evidence and recommendations for anticholinergic drugs 4.1.4.2.2 Beta-3 agonists 4.1.4.2.2.1 Summary of evidence and recommendation for mirabegron 4.1.4.2.3 Anticholinergics and beta-3 agonists: the elderly and cognition 4.1.4.2.3.1 Applicability of evidence to the general elderly population 4.1.4.2.3.2 Anticholinergic burden 4.1.4.2.3.3 Summary of evidence and additional recommendations for use of anticholinergic drugs in the elderly 4.1.4.2.4 Oestrogens 4.1.4.2.4.1 Summary of evidence and recommendation for oestrogen therapy 4.1.4.3 Surgical management 4.1.4.3.1 Bladder wall injection of botulinum toxin A 4.1.4.3.1.1 Summary of evidence and recommendations for bladder wall injection of botulinum toxin A 4.1.4.3.2 Sacral nerve stimulation 4.1.4.3.2.1 Summary of evidence and recommendation for sacral nerve stimulation 4.1.4.3.3 Cystoplasty/urinary diversion 4.1.4.3.3.1 Augmentation cystoplasty 4.1.4.3.3.2 Detrusor myectomy (bladder auto-augmentation) 4.1.4.3.3.3 Urinary diversion 4.1.4.3.3.4 Summary of evidence and recommendations for cystoplasty/urinary diversion 4.1.5 Follow-up 4.1.5.1 Recommendations for follow-up of patients with overactive bladder 4.2 Stress Urinary Incontinence 4.2.1 Epidemiology, aetiology, pathophysiology 4.2.2 Classification 4.2.3 Diagnostic evaluation 4.2.3.1 History and physical examination

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4.2.3.1.1 Summary of evidence and recommendation for history and physical examination for SUI 37 4.2.3.2 Patient questionnaires 37 4.2.3.2.1 Summary of evidence and recommendation for patient questionnaires 37 4.2.3.3 Post-void residual volume 37 4.2.3.3.1 Summary of evidence and recommendations for post-void residual volume 37 4.2.3.4 Urodynamics 38 4.2.3.4.1 Summary of evidence and recommendations for urodynamics 38 4.2.3.5 Pad testing 39 4.2.3.5.1 Summary of evidence and recommendations for pad testing 39 4.2.3.6 Imaging 39 4.2.3.6.1 Summary of evidence and recommendation for imaging 40 4.2.4 Disease management 40 4.2.4.1 Conservative management 40 4.2.4.1.1 Obesity and weight loss 40 4.2.4.1.1.1 Summary of evidence and recommendation for obesity and weight loss 40 4.2.4.1.2 Urinary containment 40 4.2.4.1.2.1 Summary of evidence and recommendations for urinary containment 40 4.2.4.1.3 Pelvic floor muscle training 41 4.2.4.1.3.1 Efficacy of pelvic floor muscle training in stress urinary incontinence 41 4.2.4.1.3.2 Efficacy of electrical stimulation 41 4.2.4.1.3.3 Long-term efficacy of pelvic floor muscle training 42 4.2.4.1.3.4 Efficacy of pelvic floor muscle training in childbearing women 42 4.2.4.1.3.5 Pelvic floor muscle training in the elderly 42 4.2.4.1.3.6 Summary of evidence and recommendations for pelvic floor muscle training 43 4.2.4.1.4 Electromagnetic stimulation 43 4.2.4.2 Pharmacological management 43 4.2.4.2.1 Oestrogen 43 4.2.4.2.1.1 Summary of evidence and recommendations for oestrogens 44 4.2.4.2.2 Duloxetine 44 4.2.4.2.2.1 Summary of evidence and recommendations for duloxetine 44 4.2.4.3 Surgical management 45 4.2.4.3.1 General considerations 45 4.2.4.3.1.1 Recommendations for surgical treatment of SUI 46 4.2.4.3.2 Surgery for women with uncomplicated stress urinary incontinence 46 4.2.4.3.2.1 Open- and laparoscopic colposuspension surgery 46 4.2.4.3.2.1.1 Summary of evidence and recommendation for open- and laparoscopic colposuspension surgery for stress urinary incontinence 47 4.2.4.3.2.2 Autologous sling 47 4.2.4.3.2.2.1 Summary of evidence and recommendation for autologous sling 47 4.2.4.3.2.3 Urethral bulking agents 48 4.2.4.3.2.3.1 Summary of evidence and recommendations for urethral bulking agents 48 4.2.4.3.2.4 Mid-urethral slings 49

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4.2.4.3.2.4.1 Summary of evidence and recommendations for mid-urethral slings 52 4.2.4.3.2.5 Other treatments for uncomplicated SUI 53 4.2.4.3.2.5.1 Summary of evidence and recommendations for other treatments for uncomplicated SUI 53 4.2.4.3.3 Surgery for women with complicated stress urinary incontinence 53 4.2.4.3.3.1 Colposuspension or sling (synthetic or autologous) following failed primary SUI surgery 54 4.2.4.3.3.1.1 Summary of evidence for surgery in those with recurrent SUI following failed primary SUI surgery 54 4.2.4.3.3.2 Adjustable slings 55 4.2.4.3.3.2.1 Summary of evidence for adjustable slings 55 4.2.4.3.3.3 External compression devices 55 4.2.4.3.3.3.1 Summary of evidence for external compression devices 56 4.2.4.3.3.4 Recommendations for complicated stress urinary incontinence 56 4.2.4.3.4 Surgery for stress urinary incontinence in special patient groups 56 4.2.4.3.4.1 Stress urinary incontinence surgery in obese women 56 4.2.4.3.4.2 Stress urinary incontinence surgery in elderly women 56 4.2.4.3.4.3 Summary of evidence and recommendations for SUI surgery in special patient groups 57 4.2.5 Follow-up 57 4.3 Mixed urinary incontinence 57 4.3.1 Epidemiology, aetiology and pathophysiology 57 4.3.2 Diagnostic evaluation 58 4.3.2.1 Summary of evidence and recommendations for the diagnosis of mixed urinary incontinence 58 4.3.3 Disease Management 58 4.3.3.1 Conservative management 58 4.3.3.1.1 Pelvic floor muscle training in mixed urinary incontinence 58 4.3.3.1.2 Bladder training 59 4.3.3.1.3 Electrical stimulation 59 4.3.3.2 Summary of evidence and recommendations for conservative management in MUI 59 4.3.3.3 Pharmacological management 59 4.3.3.3.1 Tolterodine 59 4.3.3.3.2 Duloxetine 60 4.3.3.3.3 Summary of evidence and recommendations for pharmacological management of MUI 60 4.3.3.4 Surgical management 60 4.3.3.4.1 Summary of evidence and recommendations for surgery in patients with MUI 61 4.4 Underactive bladder 61 4.4.1 Epidemiology, aetiology, pathophysiology 61 4.4.1.1 Epidemiology 61 4.4.1.2 Aetiology 62 4.4.1.3 Pathophysiology 62 4.4.2 Classification 63 4.4.3 Diagnostic evaluation 63 4.4.3.1 Symptoms associated with detrusor underactivity 63 4.4.3.2 Urodynamic studies 63

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4.4.4 Disease management 4.4.4.1 Conservative management 4.4.4.1.1 Behavioural interventions 4.4.4.1.2 Pelvic floor muscle relaxation training with biofeedback 4.4.4.1.3 Clean intermittent self-catheterisation 4.4.4.1.4 Indwelling catheter 4.4.4.1.5 Intravesical electrical stimulation 4.4.4.1.6 Intraurethral insert 4.4.4.2 Pharmacology management 4.4.4.2.1 Parasympathomimetics 4.4.4.2.2 Alpha-blockers 4.4.4.2.3 Prostaglandins 4.4.4.3 Surgical management 4.4.4.3.1 Sacral nerve stimulation 4.4.4.3.2 OnabotulinumtoxinA 4.4.4.3.3 Transurethral incision of the bladder neck 4.4.4.3.4 Reduction cystoplasty 4.4.4.3.5 Myoplasty 4.4.4.4 Summary of therapeutic evidence on detrusor underactivity 4.4.4.4.1 Summary of evidence and recommendations for underactive bladder 4.4.5 Follow-up 4.5 Bladder outlet obstruction 4.5.1 Introduction 4.5.2 Epidemiology, aetiology, pathophysiology 4.5.2.1 Epidemiology 4.5.2.2 Pathophysiology 4.5.2.3 Aetiology 4.5.3 Classification 4.5.3.1 Anatomic bladder outlet obstruction 4.5.3.2 Functional bladder outlet obstruction 4.5.3.3 Recommendation for the classification of bladder outlet obstruction 4.5.4 Diagnostic evaluation 4.5.4.1 Clinical history 4.5.4.2 Clinical examination 4.5.4.3 Uroflowmetry and post-void residual volume 4.5.4.4 Ultrasound 4.5.4.5 Magnetic resonance imaging 4.5.4.6 Electromyography 4.5.4.7 Cystourethroscopy 4.5.4.8 Urodynamics and video-urodynamics 4.5.4.9 Summary of evidence and recommendations for the diagnosis of bladder outlet obstruction 4.5.5 Disease management 4.5.5.1 Conservative management 4.5.5.1.1 Behavioural modification 4.5.5.1.2 Pelvic floor muscle training +/- biofeedback 4.5.5.1.3 Electrical stimulation 4.5.5.1.4 Use of vaginal pessary 4.5.5.1.5 Urinary containment devices 4.5.5.1.6 Urinary catheterisation 4.5.5.1.7 Intra-urethral inserts 4.5.5.1.8 Extracorporeal magnetic stimulation 4.5.5.1.9 Summary of evidence and recommendations for conservative treatment of bladder outlet obstruction 4.5.6 Pharmacologic management 4.5.6.1 Alpha-adrenergic blockers 4.5.6.2 Striated muscle relaxants 4.5.6.3 Oestrogens 4.5.6.4 Sildenafil

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4.5.6.5 Thyrotropin-releasing hormone 4.5.6.6 Summary of evidence and recommendations for pharmacologic treatment 4.5.7 Surgical treatment 4.5.7.1 Intra-sphincteric botulinum toxin injection 4.5.7.2 Sacral nerve stimulation 4.5.7.3 Pelvic organ prolapse surgery 4.5.7.4 Urethral dilatation 4.5.7.5 Urethrotomy 4.5.7.6 Bladder neck incision/resection 4.5.7.7 Urethroplasty/urethral reconstruction 4.5.7.8 Urethrolysis 4.5.7.9 Removal/excision/section/loosening of mid-urethral sling 4.5.7.9.1 Timing of sling revision 4.5.7.10 Summary of evidence and recommendations for surgical management of BOO 4.5.8 Follow up 4.6 Nocturia 4.6.1 Epidemiology, aetiology, pathophysiology 4.6.2 Classification 4.6.3 Diagnostic evaluation 4.6.3.1 Summary of evidence and recommendations for the diagnosis of nocturia 4.6.4 Disease management 4.6.4.1 Conservative management 4.6.4.1.1 Summary of evidence and recommendations for the conservative management of nocturia 4.6.4.2 Pharmacology management 4.6.4.2.1 Desmopressin 4.6.4.2.2 Anticholinergics 4.6.4.2.3 Oestrogens 4.6.4.2.4 Diuretic treatment 4.6.4.3 Surgical management 4.6.4.4 Summary of evidence and recommendations for the pharmacological management of nocturia 4.6.5 Follow-up 4.7 Pelvic organ prolapse and LUTS 4.7.1 Epidemiology, aetiology, pathophysiology 4.7.2 Classification 4.7.3 Diagnostic evaluation 4.7.3.1 Summary of evidence and recommendation for the detection of SUI in women with POP 4.7.3.2 Urodynamics in women with POP and LUTS (without stress urinary incontinence). 4.7.4 Disease management 4.7.4.1 Conservative treatment of pelvic organ prolapse 4.7.4.1.1 Pelvic floor muscle training versus lifestyle advice 4.7.4.1.2 Pelvic floor muscle training versus pelvic floor muscle training with pessary 4.7.4.1.3 Pelvic floor muscle training versus pessary only 4.7.4.1.4 Surgery versus surgery with pelvic floor muscle training 4.7.4.1.5 Summary of evidence and guidelines for the conservative treatment of pelvic organ prolapse and lower urinary tract symptoms 4.7.4.2 Pelvic organ prolapse surgery and overactive bladder 4.7.4.3 Pelvic organ prolapse surgery and bladder outlet obstruction 4.7.4.4 Pelvic organ prolapse surgery and stress urinary incontinence 4.7.4.4.1 Vaginal pelvic organ prolapse surgery in women with stress urinary incontinence 4.7.4.4.2 Abdominal pelvic organ prolapse surgery in women with stress urinary incontinence

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90 91 91 91 91 91

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4.7.4.4.3 Vaginal POP surgery in women with prolapse and occult stress urinary incontinence 4.7.4.5 Vaginal pelvic organ prolapse surgery in continent women 4.7.4.5.1 Abdominal pelvic organ prolapse surgery in continent women 4.7.4.6 Adverse events associated with combined pelvic organ prolapse and stress urinary incontinence surgery 4.7.5 Summary of evidence and recommendations for surgery in women with both pelvic organ prolapse and stress urinary incontinence 4.8 Urinary fistula 4.8.1 Epidemiology, aetiology and pathophysiology 4.8.1.1 Obstetric fistula 4.8.1.2 Iatrogenic fistula 4.8.1.2.1 Post-gynaecological surgery 4.8.1.2.2 Radiation fistula 4.8.1.2.3 Rare causes of vesico-vaginal fistula 4.8.1.3 Summary of evidence for epidemiology, aetiology and pathophysiology of urinary fistula 4.8.2 Classification 4.8.2.1 Recommendation for the classification of urinary fistula 4.8.3 Diagnostic evaluation 4.8.4 Management of fistula 4.8.4.1 Management of vesico-vaginal fistula 4.8.4.1.1 Conservative management 4.8.4.1.1.1 Spontaneous closure 4.8.4.1.1.2 Pharmacotherapies 4.8.4.1.1.3 Palliation and skin care 4.8.4.1.1.4 Nutrition 4.8.4.1.1.5 Physiotherapy 4.8.4.1.1.6 Antimicrobial therapy 4.8.4.1.1.7 Counselling 4.8.4.1.2 Surgical management 4.8.4.1.2.1 Timing of surgery 4.8.4.1.2.2 Surgical approaches 4.8.4.1.3 Management of complications of vesico-vaginal fistulae 4.8.4.2 Management of radiation fistulae 4.8.4.3 Management of ureteric fistulae 4.8.4.3.1 General principles 4.8.4.3.2 Uretero-vaginal fistulae 4.8.4.3.3 Management of urethrovaginal fistulae 4.8.4.3.3.1 Aetiology 4.8.4.3.3.2 Diagnosis 4.8.4.3.3.3 Surgical management 4.8.4.3.3.4 Flaps and neo-urethra 4.8.4.3.3.5 Martius flap 4.8.4.3.3.6 Rectus muscle flap 4.8.4.3.3.7 Alternative approaches 4.8.4.4 Summary of evidence and recommendations for the management of urinary fistula 4.9 Urethral diverticulum 4.9.1 Epidemiology, aetiology, pathophysiology 4.9.2 Classification 4.9.3 Diagnosis 4.9.3.1 Associated voiding dysfunction 4.9.4 Disease management 4.9.4.1 Surgical treatment 4.9.4.2 Management of concomitant stress urinary incontinence 4.9.4.3 Pathological findings 4.9.5 Summary of evidence and recommendations for urethral diverticulum

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5. REFERENCES

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6.

CONFLICT OF INTEREST

144

7.

CITATION INFORMATION

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1.

INTRODUCTION

Lower urinary tract symptoms (LUTS) is the overarching term encompassing storage, voiding and postmicturition symptoms [1]. Storage symptoms commonly described include frequency, urgency, nocturia and urinary incontinence (UI) (stress UI [SUI], urgency UI [UUI] and mixed UI [MUI]). Voiding symptoms include hesitancy, intermittency, slow stream, straining, splitting or spraying of the urinary stream and terminal dribble. Post-micturition symptoms include post-void dribbling and feeling of incomplete bladder emptying. Lower urinary tract symptoms are often broadly classified into clinical syndromes/entities such as overactive bladder (OAB), underactive bladder (UAB), UI, nocturia, dysfunctional voiding, or genito-urinary fistulae. Lower urinary tract symptoms are an extremely common complaint in the female population in every part of the world [2-5]. It causes a great deal of distress and embarrassment [6], as well as significant costs to both individuals and societies. Estimates of prevalence vary according to the definition and the population studied. However, there is universal agreement about the importance of the problem in terms of human suffering and economic cost [7].

1.1

Aim and objectives

These Guidelines from the European Association of Urology (EAU) Working Panel on Non-neurogenic Female LUTS are written by a multidisciplinary group, primarily for urologists, but are likely to be referred to by other professional groups. They aim to provide sensible and practical evidence-based guidance on the clinical problems associated with female LUTS rather than an exhaustive narrative review. Such reviews for UI and other LUT syndromes are already available from the International Consultation on Incontinence (ICI) [8] and other sources, so these EAU Guidelines do not describe the causation, basic science, epidemiology and psychology of LUTS/UI in detail. The focus of these Guidelines is entirely on assessment and treatment, reflecting clinical practice. These guidelines also do not consider women with LUTS caused by neurological disease, or LUTS occurring in children, as this is covered by complementary EAU Guidelines [9, 10]. The current Guidelines provide: • A clear description of the assessment and treatment of common clinical problems. This can provide the basis for thinking through a patient’s management and for planning and designing clinical services; • A brief but authoritative summary of the current state of evidence on clinical topics, complete with references to the original sources; • Clear guidance on what to do or not to do, in most clinical circumstances. This should be particularly helpful in those areas of practice for which there is little, or no, high-quality evidence. The latest edition of the guidelines has seen a significant expansion of scope from ‘urinary incontinence’ to ‘nonneurogenic female LUTS’. The primary consideration here was to include the significant population of women with functional urological conditions not necessarily associated with UI that were hitherto not accounted for in previous guidelines. Secondary considerations were to align more cohesively with the existing Non-neurogenic Male LUTS Guideline. As a consequence of the anatomical and physiological differences between the male and female LUT, the prevalence, pathophysiology, diagnostic approach and management of male and female LUTS differ widely. For that reason, the EAU Guidelines Office decided to provide gender-specific guidelines on LUTS and UI going forward. As a result, the section on post-prostatectomy UI has been moved to the Non-neurogenic Male LUTS Guideline. This reconfiguration has also seen some additional sections added to this Guideline (including nonobstetric fistulae, female bladder outlet obstruction [BOO], UAB and nocturia) and over the course of the next two or three iterations the scope is likely to widen further.

1.2

Panel composition

The EAU Non-neurogenic Female LUTS Panel consists of a multidisciplinary group of experts, including urologists, a uro-gynaecologist, a urodynamic scientist and a physiotherapist. All experts involved in the production of this document have submitted potential conflict of interest statements which can be viewed on the EAU website: https://uroweb.org/guideline/non-neurogenic-female-luts/. The Panel acknowledge the support of Mrs. M. de Heide (Bekkenbodem4all), Mrs. T. van den Bos (Bekkenbodem4All), Mrs. M.L van Poelgeest-Pomfret (World Federation for Incontinence and Pelvic Problems [WFIP]) and Dr. H. Cobussen-Boekhorst (nurse practitioner) in the development of these guidelines.

1.3

Available publications

A quick reference document (Pocket Guidelines) is available, both in print and as an app for iOS and Android devices. These are abridged versions which require consideration together with the full text versions. All

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documents are accessible through the EAU website: https://uroweb.org/guideline/non-neurogenic-female-luts/.

1.4

Publication history

The first EAU Urinary Incontinence Guidelines were published in 2001. The guideline has been modified since to broaden its scope specifically to include other female LUTS as of 2021.

2.

METHODS

2.1

Introduction

For the 2021 Non-neurogenic Female LUTS Guideline, the existing text of the 2018 Urinary Incontinence Guidelines was re-structured and significantly expanded. The PICO question-based format of the text was modified to improve readability, although the underlying PICO structure still informs search strategies. Databases searched for the 2021 update included Medline, EMBASE, and the Cochrane Libraries, covering a time frame between Jan 1st, 2000 and June 16th, 2020 with a focus on high level evidence only (systematic reviews and meta-analyses). Detailed search strategies are available online: https://uroweb.org/guideline/non-neurogenic-female-luts/?type=appendices-publications. For the 2021 edition of the Guidelines a number of de novo systematic reviews have been undertaken by the Panel on the subjects of OAB syndrome and the diagnosis and treatment of female BOO [11, 12]. Full publication of the systematic review results are pending; however, the preliminary results have informed the corresponding sections of this Guidelines update. For each recommendation within the guidelines there is an accompanying online strength rating form, the basis of which is a modified GRADE methodology [13, 14]. Each strength rating form addresses a number of key elements, namely: 1. the overall quality of the evidence which exists for the recommendation; references used in this text are graded according to a classification system modified from the Oxford Centre for Evidence-Based Medicine Levels of Evidence [15]; 2. the magnitude of the effect (individual or combined effects); 3. the certainty of the results (precision, consistency, heterogeneity and other statistical or study related factors); 4. the balance between desirable and undesirable outcomes; 5. the impact of patient values and preferences on the intervention; 6. the certainty of those patient values and preferences. These key elements are the basis which panels use to define the strength rating of each recommendation. The strength of each recommendation is represented by the words ‘strong’ or ‘weak’ [16]. The strength rating forms will be available online. Additional information can be found in the general Methodology section of this document, and online at the EAU website: https://uroweb.org/guidelines/policies-and-methodological-documents/. A list of Associations endorsing the EAU Guidelines can also be viewed online at the above address.

2.2

Review

The guideline has been peer reviewed prior to publication in 2021.

2.3 • • •

Future goals A systematic review on the topic of Pelvic Organ Prolapse (POP); A systematic review on synthetic/mesh-related mid-urethral sling (MUS) complications; A systematic review on the diagnosis and treatment of underactive bladder (UAB) in women.

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3.

DIAGNOSTIS

3.1

History and physical examination

Taking a thorough clinical history is fundamental to the process of clinical evaluation. Despite the lack of highlevel evidence to support it, there is universal agreement that taking a history should be the first step in the assessment of anyone with LUTS. The history should include a full evaluation of LUT symptoms (storage, voiding and post-micturition symptoms), sexual, gastrointestinal and neurological symptoms. Details of urgency episodes, the type, timing and severity of UI, and some attempt to quantify symptoms should also be made. The history should help to categorise LUTS as storage, voiding and post-void symptoms, and classify UI as SUI, UUI, MUI or overflow incontinence, the latter being defined as ‘the complaint of UI in the symptomatic presence of an excessively (over-) full bladder (no cause identified)’ [17]. It should also identify patients who need referral to an appropriate clinic/specialist. These may include patients with associated pain, haematuria, a history of recurrent urinary tract infection (UTI), pelvic surgery or radiotherapy, constant leakage suggesting a fistula (see Section 4.8), new-onset enuresis or suspected neurological disease. A neurological, obstetric and gynaecological history may help to understand the underlying cause and identify factors that may impact on treatment decisions. Guidance on history taking and diagnosis in relation to UTIs, neuro-urological conditions and chronic pelvic pain can be found in the relevant EAU Guidelines [9, 18, 19]. The patient should also be asked about other co-morbidities as well as smoking status, previous surgical procedures and for the details of current medications, as these may impact on symptoms of LUTS. Similarly, there is little evidence from clinical trials that carrying out a clinical examination improves outcomes, but wide consensus suggests that it remains an essential part of assessment of patients with LUTS. It should include abdominal examination, to detect an enlarged urinary bladder or other abdominal mass, and digital examination of the vagina and/or rectum. Examination of the perineum in women includes an assessment of oestrogen status, pelvic floor muscle (PFM) function and a careful assessment of any associated POP. A cough stress test is necessary to look for SUI. The urethral mobility can be assessed visually and with an Ulmsten/ Pinch or Marshall/Bonney test. Pelvic floor contraction strength can also be assessed digitally. A focused neuro-urological examination should also be routinely undertaken. 3.1.1

Summary of evidence and recommendation for history taking and physical examination

Summary of evidence History taking including symptoms and comorbidities and a focussed physical examination is an essential part of the evaluation of a woman with LUTS.

Recommendation Take a complete medical history including symptoms and comorbidities and a focused physical examination in the evaluation of women with lower urinary tract symptoms.

3.2

LE 4

Strength rating Strong

Patient questionnaires

This section includes symptom scores, symptom questionnaires/scales/indices, patient-reported outcome measures (PROMs) and health-related quality of life (HRQoL) measures. The latter include generic or conditionspecific measures. Questionnaires should have been validated for the language in which they are being used, and, if used for outcome evaluation, should have been shown to be sensitive to change. The US Food and Drug Administration (FDA) published guidance for industry on patient-reported outcome instruments (questionnaires) in 2009 [20]. Although many studies have investigated the validity and reliability of urinary symptom questionnaires and PROMs most of these studies include mixed populations (men and women). This limits the extent to which results and conclusions from these studies can be applied to particular LUT syndromes in women. Some questionnaires (ICIQ-FLUTS, QUID, 3IQ, ICIQ-SF) have potential to discriminate UI types in women [21-23]. Others have been developed to measure symptoms and bother in OAB (OABQ-SF, B-SAQ) and other specific conditions. Some questionnaires are responsive to change and may be used to measure outcomes, though evidence on their sensitivity is inconsistent [24, 25]. No evidence was found to indicate whether use of QoL or condition-specific questionnaires has an impact on outcome of treatment. Detailed description of the different urinary symptoms questionnaires and PROMs is beyond the scope of this guideline. For more information we recommend the 6th ICI review on patient reported outcomes assessment [26]. To date, there is no one questionnaire that fulfils all requirements for assessment of women

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with LUTS. Clinicians must evaluate the tools that exist, for use alone or in combination, for assessment and monitoring of treatment outcome [27]. The questionnaires can be found on the following websites: www.iciq.net, https://eprovide.mapi-trust.org, www.pfizerpcoa.com, www.ncbi.nlm.nih.gov. 3.2.1

Summary of evidence and recommendation for patient questionnaires

Summary of evidence Validated condition-specific symptom scores assist in the screening for, and categorisation of LUTS. Validated symptom scores measure the severity of UI and LUTS.

LE 3 3

Both condition-specific and general health status questionnaires measure current health status and change following treatment. Patient questionnaires cannot replace a detailed patient consultation and should only be used as part of a complete medical history.

3

Recommendation Use a validated and appropriate questionnaire as part of the standardised assessment of female lower urinary tract symptoms.

3.3

4

Strength rating Strong

Bladder diaries

Measurement of the frequency and severity of LUTS is an important step in the evaluation and management of lower urinary tract (LUT) dysfunction. Bladder diaries are a semi-objective method of quantifying symptoms, such as frequency of UI events, number of nocturia episodes etc. They also quantify urodynamic variables, such as voided volume, 24-hour urine volume or nocturnal total urine volume. Voiding diaries are also known as micturition time charts, frequency/volume charts and bladder diaries. Discrepancy between diary recordings and the patient rating of symptoms, e.g. frequency of UI, can be useful for patient counselling. In addition, fluid intake and voided volume measurement can be used to support diagnoses and management planning, for example in OAB, and for identifying polyuria, either 24-hour or nocturnal polyuria. Diaries can also be used to monitor treatment response and are widely used in clinical trials. In patients with severe UI, a bladder diary is unlikely to accurately report 24-hour urine output. Consensus terminology is now well-defined and widely accepted [1, 28]. However, the terms micturition diary, frequency volume chart, bladder diary and voiding diary, have been used interchangeably for many years, but only bladder diaries include information on fluid intake, times of voiding, voided volumes, UI episodes, pad usage, degree of urgency and degree of UI recorded for at least 24 hours. When reviewing the evidence all synonymous search terms have been included. Two studies have demonstrated the reproducibility of diaries in both men and women [29, 30]. Another two studies have shown the feasibility, reliability and validity of the bladder diary [31, 32]. Further studies have demonstrated variability of diary data within a 24-hour period and compared voided volumes recorded in diaries with those recorded by uroflowmetry [33, 34]. Another study found that keeping a bladder diary had a therapeutic benefit [35]. A number of observational studies have demonstrated a close correlation between data obtained from bladder diaries and standard symptom evaluation [36-39]. The optimum number of days required for bladder diaries appears to be based on a balance between accuracy and compliance [40, 41]. Diary durations between 3 and 7 days are routinely used in the literature. 3.3.1

Summary of evidence and recommendations for bladder diaries

Summary of evidence Bladder diaries of three to seven days duration are a reliable tool for the objective measurement of mean voided volume, day- and night-time frequency, and UI episode frequency. Bladder diaries are sensitive to change and are a reliable outcome measure.

Recommendations Ask patients with lower urinary tract symptoms to complete a bladder diary as part of the standardised assessment of female LUTS. Use a bladder diary with a duration of at least three days.

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LE 2b 2b

Strength rating Strong Strong

13

3.4

Urinalysis and urinary tract infection

Reagent strip (‘dipstick’) urinalysis may indicate proteinuria, haematuria or glycosuria or suggest UTI requiring further assessment. Refer to the Urological Infections Guidelines for diagnosis and treatment of UTI [18]. Urine dipstick testing is a useful adjunct to clinical evaluation in patients in whom urinary symptoms are suspected to be due to UTI. Urinalysis negative for nitrite and leucocyte esterase may exclude bacteriuria in women with LUTS [42], and should be included, with urine culture when necessary, in the evaluation of all patients with LUTS. Urinary incontinence or worsening of LUTS may occur during a UTI [43] and existing UI may worsen during UTI [44]. The rate and severity of UI was unchanged after eradication of asymptomatic bacteriuria in nursing home residents [45]. 3.4.1

Summary of evidence and recommendations for urinalysis

Summary of evidence Urinalysis negative for nitrite and leucocyte esterase may exclude bacteriuria in women with LUTS. Urinary incontinence may be a symptom during a UTI, and LUTS may deteriorate during a UTI. The presence of a UTI worsens existing symptoms of UI. Elderly nursing home patients with UI do not benefit from treatment of asymptomatic bacteriuria. Recommendations Perform urinalysis as a part of the initial assessment of a patient LUTS. If a urinary tract infection is present with LUTS, reassess the patient after treatment. Do not routinely treat asymptomatic bacteriuria in elderly patients to improve urinary incontinence.

3.5

LE 3 3 3 2

Strength rating Strong Strong Strong

Post-void residual volume

Post-void residual (PVR) volume is the amount of urine that remains in the bladder after voiding. It indicates poor voiding efficiency, which may result from a number of contributing factors. Assessment of PVR is important because it may worsen symptoms and, more rarely, may be associated with UTI, upper urinary tract (UUT) dilatation and renal insufficiency. Both BOO and detrusor underactivity (DU) potentially contribute to the development of PVR. Post-void residual can be measured by catheterisation or ultrasound (US). The prevalence of PVR in patients with LUTS is uncertain, partly because of the lack of a standard definition of an abnormal PVR volume. Bladder voiding efficiency (BVE) is the proportion of the total bladder volume that is voided by the patient. The BVE can be defined as a percentage: BVE = (voided volume/[VV]+PVR) × 100. This may be a more reliable parameter to evaluate poor voiding [46]. Most studies investigating PVR assessed mixed populations. Although some studies have included women with UI and men and women with LUTS, they have also included children and adults with neurogenic UI. In general, the data on PVR can be applied with caution to women with non-neurogenic LUTS. The results of studies investigating the best method of measuring PVR [45, 47-51] have led to the consensus that US measurement of PVR is preferable to catheterisation due to its favourable risk-benefit profile. In peri- and post-menopausal women without significant LUTS or pelvic organ symptoms, 95% of women had a PVR < 100 mL [52]. In women with UUI, a PVR > 100 mL was found in only 10% of cases [53]. Other research has found that a high PVR is associated with POP, voiding symptoms and an absence of SUI [52, 54-56]. In women with SUI, the mean PVR was 39 mL measured by catheterisation and 63 mL measured by US, with 16% of women having a PVR > 100 mL [57]. Some authors have suggested that it is reasonable to consider a PVR of > 100 mL to be significant, although many women may remain asymptomatic and hence it is imperative to consider the clinical context [53]. There is no consensus on what constitutes a significant PVR in women; therefore, the Panel suggests the additional use of BVE. 3.5.1

Summary of evidence and recommendations for post-void residual

Summary of evidence Lower urinary tract symptoms are associated with a higher PVR compared to asymptomatic population groups.

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LE 2

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Recommendations Measure post-void residual volume (PVR) in patients with LUTS during initial assessment. Use ultrasound to measure PVR. Monitor PVR in patients receiving treatments that may cause or worsen voiding dysfunction. Provide Bladder Voiding Efficiency as an additional parameter when measuring PVR.

3.6

Strength rating Strong Strong Strong Weak

Urodynamics

Urodynamic testing is widely used as an adjunct to clinical diagnosis, in the belief that it may help to provide or confirm diagnosis, predict treatment outcome or facilitate discussion during counselling. The simplest form of urodynamic evaluation is uroflowmetry. The maximum flow rate (Qmax), the volume voided and the shape of the curve in addition to the PVR volume (see above) are the most important aspects to be assessed [26]. The bladder should be sufficiently full because of the volume dependency of Qmax [58, 59]. A minimum voided volume of 150 mL is advised in males, but there is very little evidence to suggest a volume threshold in females. It is of relevance to ask the patient whether or not the voiding was representative. Invasive urodynamic tests are often performed prior to invasive treatment of LUTS. These tests include multichannel cystometry and pressure-flow studies, ambulatory monitoring and video-urodynamics, and different tests of urethral function, such as urethral pressure profilometry and Valsalva leak point pressure (VLPP). The ICS and the United Kingdom Continence Society provide standards to optimise urodynamic test performance and reporting [60, 61]. A characteristic of a good urodynamic study is that the patient’s symptoms are replicated, recordings are checked for quality control and results interpreted in the context of the clinical problem, remembering that there may be physiological variability within the same individual [60]. Noninvasive alternatives for measurement of detrusor pressure and BOO include transabdominal wall near-infrared spectroscopy and US detrusor wall thickness analysis, but as yet these techniques have not been adopted into routine clinical practice [26]. In common with most physiological tests there is variability in urodynamic results. This has consequences for the reproducibility, diagnostic accuracy and predictive value of urodynamic testing (UDS). It has been stated that, at least in the case of cystometry and pressure-flow studies, one set of measurements suffice, but only if the patient’s symptoms have been replicated [60]. It can nevertheless be sometimes necessary or advisable to repeat the urodynamic measurements. The risk-benefit profile of repeating urodynamic testing should always be considered. Further condition-specific information regarding the role of urodynamic testing in OAB, SUI, BOO and UAB can be found in respective sections of this Guideline. 3.6.1 Variability Contradictory findings were reported in studies assessing same-session repeatability of cystometric and pressure-flow studies [62, 63]. There is also conflicting evidence about the reproducibility of maximum urethral closure pressure (MUCP) measurement [64, 65]. One method of recording MUCP cannot be compared meaningfully to another [65, 66]. Valsalva leak point pressure measurement is not standardised and there is minimal evidence about its reproducibility. No studies on the reproducibility of ambulatory monitoring in nonneurological patients have been published [26]. 3.6.2 Diagnostic accuracy Clinical diagnosis and cystometric findings often do not correlate [67, 68] and asymptomatic women may have abnormalities on urodynamic testing. As the urodynamic diagnosis is often taken as the benchmark in the assessment of LUT function, this implies that the evaluation of other tests of LUT function may be biased as a result. The diagnostic accuracy of urethral pressure profilometry [69] and urethral retro-resistance pressure measurement in SUI is generally poor [26]. Valsalva leak point pressure did not reliably assess UI severity in a cohort of women selected for surgical treatment of SUI [70]. Urethral pressure reflectometry may have greater diagnostic accuracy but its clinical role remains unclear [71]. Ambulatory urodynamics may detect unexpected physiological variance from normal more often than conventional cystometry, but the clinical relevance of this is also uncertain [72, 73]. A pressure-flow study, that is, the simultaneous measurement of flow rate and detrusor pressure during voiding, can reveal whether a poor flow rate and PVR’s are due to BOO, poor bladder contraction strength (DU) or a combination of both. Also, it may provide information on the degree of pelvic floor relaxation and thus diagnose dysfunctional voiding. As with uroflowmetry, its representativeness must be verified. Several proposals to define BOO in women have been made. These definitions are based on detrusor pressure values,

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either the value at Qmax or the maximum value, and the Qmax value, either during the pressure-flow study or during uroflowmetry; sometimes combined with the findings during fluoroscopic imaging (see Section 4.5.4.8 for more detailed information) [74, 75]. Unlike the situation in men, there is no generally accepted definition or nomogram in women. Bladder contraction strength parameters are derived from the detrusor pressure and flow rate values during a pressure flow study or from stop tests [75], but again validation is poor. In addition, while these parameters estimate the strength of the contraction, they ignore its speed and persistence (see Section 4.4.3.2 for more detailed information) [76]. A video-urodynamic study can be useful to detect the site of obstructed voiding, which may be anatomical or functional [77]. Also, video-urodynamics may detect a bladder diverticulum or gross reflux as a pressure absorbing reservoir. 3.6.3 Predictive value Performing urodynamic evaluation is only useful if it leads to more effective clinical care and better outcomes. A Cochrane review of eight randomised controlled trials (RCTs) showed that use of urodynamic tests in women with UI increased the likelihood of prescribing drugs and did not increase the likelihood of undergoing surgery. However, there was no evidence that this influence on decision-making altered the clinical outcome of treatment [78]. Most RCTs addressed the utility of urodynamic tests on SUI only, include women with uncomplicated SUI. A meta-analysis including four RCTs comparing surgical outcomes in women with selfreported SUI (or stress-predominant MUI) who were investigated via urodynamics with women who had office evaluation only found that there was no difference in cure and complication rate [79]. On the other hand, in a large retrospective multicentre study it was found that only 36% of patients were defined as ‘‘uncomplicated’’ according to the definitions used in large RCTs [80]. The urodynamic observations were not consistent with the pre-urodynamic diagnosis in 1,276 out of 2,053 patients (62.2%). Voiding dysfunctions were urodynamically diagnosed in 394 patients (19.2%) and planned surgery was cancelled or modified in 304 patients (19.2%), due to the urodynamic findings [81]. The predictive value of urethral function tests remains unclear. In observational studies, there was no consistent correlation between the results of these tests and subsequent success or failure of SUI surgery [37-39, 82]. The same was true in a secondary analysis of an RCT [83]. The presence of pre-operative DO in women with stress-predominant MUI has been associated with postoperative UUI but did not predict overall treatment failure following MUS surgery or colposuspension [83]. The urodynamic diagnosis of detrusor overactivity (DO) had no predictive value for treatment response in studies on fesoterodine, onabotulinumtoxinA and sacral nerve stimulation (SNS) in patients with OAB symptoms [84-87]. Augmentation cystoplasty aims to abolish DO, improve bladder compliance and increase functional bladder capacity but there is no evidence to guide whether or not pre-operative urodynamics is predictive of outcome. Most clinicians would however consider pre-operative urodynamics as essential prior to contemplating augmentation cystoplasty. A pressure-flow study is capable of discriminating BOO from DU as a cause of voiding dysfunction. The predictive value of parameters derived from such a study for voiding dysfunction after a surgical procedure for SUI is however low. A low pre-operative flow rate and a low detrusor voiding pressure have been shown to correlate with voiding dysfunction after a tension-free vaginal tape (TVT) and an autologous fascial sling procedure, respectively [88-90]. Bladder contraction strength parameters combining flow rate and detrusor pressure values only poorly predicted voiding dysfunction after autologous fascial sling [91]. Post-hoc analysis of two high-quality surgical trials on TVT, Burch colposuspension and autologous fascial sling showed that no pre-operative urodynamic parameter could predict post-operative voiding dysfunction in a selected population of women with low pre-operative PVR [92, 93]. The Panel recognises that it may be valuable to use urodynamic test results to select the optimum management strategy; however, there is inconsistent evidence regarding the predictive value of such tests. When urodynamics and clinical assessment (i.e. by history and examination) are in disagreement, there needs to be a careful re-evaluation of the clinical symptoms of the patient and the investigation results to ensure that the diagnosis is correct before invasive treatments are contemplated.

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3.6.4

Summary of evidence and recommendations for urodynamics

Summary of evidence Most urodynamic parameters show variability within the same session and over time, and this may limit their clinical interpretation. Different techniques of measuring urethral function may have good test-retest reliability, but do not consistently correlate to other urodynamic tests or to the severity of UI. There may be inconsistency between history and urodynamic results. Urodynamic diagnosis of DO does not influence treatment outcomes in patients with OAB. Pre-operative urodynamics in women with uncomplicated, clinically demonstrable, SUI does not improve the outcome of surgery for SUI. There is no consistent correlation between the result of urethral function tests and subsequent success or failure of SUI surgery. There is no consistent evidence that pre-operative DO is associated with surgical failure of MUS in women. The presence of pre-operative DO may be associated with persistence of urgency post-operatively. Recommendations Adhere to ‘Good Urodynamic Practice’ standards as described by the International Continence Society when performing urodynamics in patients with LUTS. Do not routinely carry out urodynamics when offering treatment for uncomplicated stress urinary incontinence. Do not routinely carry out urodynamics when offering first-line treatment to patients with uncomplicated overactive bladder symptoms. Perform urodynamics if the findings may change the choice of invasive treatment. Do not use urethral pressure profilometry or leak point pressure to grade severity of urinary incontinence as they are primarily tests of urethral function.

3.7

LE 3 3 3 1a 1b 3 3 3

Strength rating Strong Strong Strong Weak Strong

Pad testing

Measurement of urine loss using an absorbent pad worn over a set period of time or during a protocol of physical exercise can be used to quantify the presence and severity of UI, as well as a patient’s response to treatment. The clinical utility of pad tests for people with UI has been assessed in two systematic reviews [94, 95]. A one-hour pad test using a standardised exercise protocol and a diagnostic threshold of 1.4 g shows good specificity but lower sensitivity for symptoms of SUI and MUI. A 24-hour pad test using a threshold of 4.4 g is more reproducible but is difficult to standardise with variation according to activity level [96]. A pad test with a specific short graded exercise protocol also has diagnostic value but a negative test should be repeated with the degree of provocation increased [97]. The usefulness of pad tests in quantifying severity and predicting outcome of treatment is uncertain [94, 98, 99]. Pad tests are responsive to change following successful treatment [100]. Pad testing using a standardised bladder volume (50% of cystometric capacity) has been suggested to allow for a more reliable assessment of UI in a small study including 25 women [101]. There is no evidence that one type of pad test is superior to another. 3.7.1

Summary of evidence and recommendations for pad testing

Summary of evidence A pad test can diagnose UI accurately. Standardisation of bladder volume and degree of provocation improves reproducibility. Twenty-four hours is sufficient duration for home-based testing balancing diagnostic accuracy and adherence. Change in leaked urine volume on pad tests can be used to measure treatment outcome. Pad tests can be a useful tool in the research setting and are an optional investigation in clinical practice.

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LE 2 2 2 2 4

17

Recommendations Use a pad test of standardised duration and activity protocol. Use a pad test when quantification of urinary incontinence is required, especially to assess response to treatment.

3.8

Strength rating Strong Weak

Imaging

Imaging improves our understanding of the anatomical and functional abnormalities that may cause LUTS. In clinical research, imaging is used to understand the relationship between anatomy and function, between conditions of the central nervous system (CNS) or of the LUT, and to investigate the relationship between LUT and pelvic floor imaging and treatment outcomes. Ultrasound and magnetic resonance imaging (MRI) have largely replaced X-ray imaging in the evaluation of the pelvic floor. Ultrasound is preferred to MRI because of its ability to produce three-dimensional and four-dimensional (dynamic) images at lower cost and wider availability. In general, there is no need for UUT imaging unless a high-pressure bladder, severe POP or chronic urinary retention is suspected or diagnosed or abnormal renal function tests are observed. In cases of suspected UI caused by an UUT anomaly or uretero-vaginal fistula, UUT imaging (intravenous urography or CT scan) may be indicated [102]. 3.8.1 Ultrasound Ultrasonography of the LUT plays a role in the differential diagnosis of women with LUTS, when there is a suspicion of bladder tumour, stones, etc. and in cases presenting with haematuria. Ultrasonography has been used in the evaluation of UI and pelvic floor since the 1980s. Different imaging approaches, such as abdominal, transvaginal, transrectal, perineal and transurethral are described. The bladder neck and urethra are easily visible and measurements can be done at rest, during straining, coughing and during pelvic floor contraction. Ultrasonography can be used to assess PFMs and their function. Contraction of the pelvic floor results in displacement of pelvic structures that can easily be imaged on US. Integrity of the levator ani muscle can be determined by 3D transperineal US. The specific role of US is discussed in the condition-specific sections of this guideline. 3.8.2 Detrusor wall thickness As OAB syndrome is linked to DO, it has been hypothesised that frequent detrusor contractions may increase detrusor/bladder wall thickness (DWT/BWT). Transvaginal US seems to be more accurate with less interobserver variability than transabdominal and transperineal approaches [103]. Several cut-off points have been suggested, from 4.4 to 6.5 mm. Other studies are contradictory and did not find this correlation. No consensus exists as to the relationship between OAB and increased BWT/DWT [104], and there is no evidence that BWT/ DWT imaging improves management of OAB in practice. There is no widely accepted, standardised bladder volume for bladder wall thickness measurement. In a retrospective study including 227 women with symptoms of voiding difficulty (hesitancy, intermittency and poor stream), 74 (32.6%) were diagnosed with voiding dysfunction on the basis of free uroflowmetry and residual urine. While controlling for the effect of DO, the relationships between DWT and different parameters of voiding function in pressure–flow studies and free uroflowmetry were examined. The results indicated that DWT was not associated with any urodynamic parameters that may indicate BOO [105]. 3.8.3 Magnetic resonance imaging There is a general consensus that MRI provides good global pelvic floor assessment, including POP, defecatory function and integrity of the pelvic floor support [106]. However, there is a large variation in MRI interpretation between observers [107] and little evidence to support its clinical usefulness in the management of LUTS/UI. There is no conclusive evidence that MRI evaluation of POP is more clinically useful than vaginal examination. Studies have assessed the use of imaging to assess the mechanism of MUS insertion for SUI. One study suggested that MUS placement decreased mobility of the mid-urethra but not of the bladder neck [108]. Following MUS, a wider gap between pubic symphysis and sling (assessed by imaging) has been shown to correlate with a lower chance of cure of SUI [109].

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3.8.4

Summary of evidence and recommendation for imaging

Summary of evidence There is no consistent evidence that routine urinary tract imaging is useful in the evaluation or management of lower urinary tract symptoms. There is no consistent evidence that bladder (detrusor) wall thickness measurement is useful in the management of OAB.

Recommendation Do not routinely carry out imaging of the upper or lower urinary tract as part of the assessment of lower urinary tract symptoms.

4.

DISEASE MANAGEMENT

4.1

Overactive bladder

LE 3 3

Strength rating Strong

4.1.1 Epidemiology, aetiology, pathophysiology Overactive bladder is defined by the ICS as ‘urinary urgency, usually accompanied by frequency and nocturia, with or without UUI, in the absence of urinary tract infection (UTI) or other obvious pathology’ [110]. Overactive bladder is a chronic condition and can have debilitating effects on QoL. The hallmark urodynamic feature is DO, although this may not be demonstrated in a large proportion of OAB patients, which may, in part, be due to failure to reproduce symptoms during urodynamic assessment. The EPidemiology of InContinence (EPIC) study was one of the largest population-based surveys that studied the prevalence of LUTS and OAB [111]. Conducted in five countries, including Canada, Germany, Italy, Sweden, and the UK, it was a cross-sectional telephone survey of adults aged > 18 years. The study included over 19,000 participants and demonstrated an overall prevalence of OAB symptoms of 11.8% (10.8% in men and 12.8% in women). Other studies have reported prevalence of up to 30–40%, with rates generally increasing with age [5]. Various theories have been proposed to explain the pathophysiology of OAB, mainly relating to imbalances in inhibitory and excitatory neural pathways to the bladder, or the sensitivity of bladder muscle receptors. However, no definite identifiable cause has been established. 4.1.2 Classification Overactive bladder is generally classified into ‘wet’ and ‘dry’, based on the presence or absence of associated UI. 4.1.3 Diagnostic evaluation The evaluation of a patient with symptoms of OAB follows the general pathway of evaluation of the female LUTS patient. 4.1.3.1 Bladder diaries Diaries are particularly helpful in establishing and quantifying symptoms of frequency, urgency and UI, and may be valuable in assessing change over time or response to treatment. A number of observational studies have demonstrated a close correlation between data obtained from bladder diaries and standard symptom evaluation [36-39]. The optimum number of days required for bladder diaries appears to be based on a balance between accuracy and compliance. Diary durations between 3 and 7 days are routinely used in the literature. 4.1.3.2 Urodynamics Urodynamics is essential in establishing the presence of DO, but its absence does not preclude the diagnosis of OAB which is based on symptoms alone. A Cochrane review of seven RCTs showed that use of urodynamic tests increased the likelihood of prescribing drugs or avoiding surgery. However, there was no evidence that this influence on decision-making altered the clinical outcome of treatment [112]. A sub-analysis of an RCT comparing fesoterodine to placebo [84, 85] showed that the urodynamic diagnosis of DO had no predictive value for treatment response.

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4.1.3.3

Summary of evidence and recommendations regarding associated conditions

Summary of evidence Bladder diaries of three to seven days duration may be helpful in quantifying symptoms of OAB, and assessing response to treatment. Urodynamic diagnosis of DO does not influence treatment outcomes in patients with OAB.

Recommendations Request that patients complete at least a three-day bladder diary at initial valuation and before each therapeutic intervention for overactive bladder (OAB). Do not routinely carry out urodynamics when offering first-line treatment to patients with uncomplicated OAB symptoms.

LE 3 1a

Strength rating Strong Strong

4.1.4 Disease management 4.1.4.1 Conservative management In clinical practice, it has long been the convention that non-surgical therapies are recommended first because they usually carry the lowest risk of harm. While this remains true for non-pharmacological conservative treatments (e.g. pelvic floor muscle training [PFMT]), increasing concerns regarding the adverse events of some pharmacological treatments used to treat LUTS (e.g. anticholinergic drugs), particularly regarding cognitive function have emerged and patients should be fully counselled regarding this potential risk. 4.1.4.1.1 Addressing underlying disease/cognitive impairment Lower urinary tract symptoms, especially in the elderly, have been associated with multiple comorbid conditions including: • cardiac failure; • chronic renal failure; • diabetes; • chronic obstructive pulmonary disease; • neurological disease; • general cognitive impairment; • sleep disturbances, e.g. sleep apnoea; • depression; • metabolic syndrome. It is possible that improvement of associated disease may reduce the severity of urinary symptoms. However, this is often difficult to assess as patients frequently suffer from more than one condition. In addition, interventions may be combined and individualised, making it impossible to decide which alteration in an underlying disease has affected a patient’s symptoms. One study involving middle-aged women with type 1 diabetes mellitus showed that 10% of these women had UUI. The study showed no correlation between earlier intensive treatment of type 1 diabetes mellitus and the prevalence of UI in later life vs. conventional treatment [113]. 4.1.4.1.1.1 Summary of evidence and recommendation regarding associated conditions Summary of evidence There is a lack of evidence that improving any associated comorbid condition improves OAB.

Recommendation Review any new medication associated with the development or worsening of UI.

LE 3

Strength rating Weak

4.1.4.1.2 Adjustment of other medication Although LUTS are listed as an adverse effect of many drugs in drug compendia, this mainly derives from uncontrolled individual patient reports and post-marketing surveillance. Few controlled studies have used the occurrence of LUTS as a primary outcome, or were powered to assess the occurrence of statistically significant LUTS or worsening rates against placebo. In most cases, it is therefore not possible to be sure that any drug causes OAB/LUTS. 20

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A structured literature review failed to identify any studies addressing whether adjustment of specific medications could alter existing symptoms of OAB. Also, there is little evidence relating to the occurrence or worsening of OAB in relation to prescription of any specific drugs. 4.1.4.1.2.1 Summary of evidence and recommendations for adjustment of non-LUTS medication Summary of evidence There is very little evidence that alteration of non-uroselective medications can cure or improve symptoms of OAB.

Recommendations Take a history of current medication use from all patients with overactive bladder (OAB). Review any new medication associated with the development or worsening of OAB symptoms.

LE 3

Strength rating Strong Weak

4.1.4.1.3 Urinary containment Urinary containment is important for people with OAB-wet or UUI when active treatment does not cure the problem, is delayed, or when it is not available or not possible. Some individuals may prefer urinary containment rather than to undergo active treatment with its associated risks. Containment includes the use of absorbent pads, urinary catheters, external collection devices and intravaginal devices. Detailed literature summaries can be found in the current ICUD monograph [114] and in a European Association of Urology Nurses guidance document [115]. A systematic review of six RCTs comparing different types of pads found that pads filled with superabsorbent material were better than standard pads, whilst evidence that disposable pads were better than washable pads was inconsistent [116]. A series of three crossover RCTs examined performance of different pad designs for differing populations [117, 118]. For women with light UI, disposable insert pads (within washable pouch pants) were most effective. In adults with moderate/severe UI, disposable pull-up pants were more effective for women. A Cochrane review summarised three RCTs comparing different types of long-term indwelling catheters and found no evidence that one catheter material or type of catheter was superior to another [119]. A systematic review of non-randomised studies found no differences in UTI outcome or UUT changes between use of suprapubic or urethral catheter drainage; however, patients with suprapubic catheters were less likely to have urethral complications [120]. Clean intermittent self-catheterisation (CISC) is the most commonly used therapy to manage high PVR volumes and urinary retention [115]. It reduces the risk of complications such as UTI, UUT deterioration, bladder stones and overflow UI etc. It has not yet been established whether the incidence of UTI, other complications and user satisfaction are affected by either sterile or clean IC, coated or uncoated catheters or by any other strategy [121]. The use of hydrophilic catheters may be associated with a lower rate of UTI, but further evidence is needed, as most of it comes from neurogenic patients [122]. The average frequency of catheterisation is four to six times per day [123] and the catheter sizes most often used are 12-16 Fr. In aseptic IC, an optimum frequency of five times showed a reduction of UTI [123]. Frequency of catheterisation needs to be based on individual need and capability, to prevent chronic and repeated over-filling of bladder [124]. Thorough counselling regarding techniques, frequency, equipment and adverse effects of CISC should be given to all potential patients in line with good medical practice. For people using CISC, a Cochrane review found no evidence that one type of catheter or regimen of catheterisation was better than another [125]. However, there is recent evidence from a narrative review suggesting that in certain populations using single-use catheters may reduce urethral trauma and UTI [126]. A Cochrane review summarising five trials comparing bladder washout policies in adults with indwelling urinary catheters found inconsistent evidence of benefit [127]. A further Cochrane review summarising eight trials testing whether antibiotic prophylaxis was beneficial for adults using CISC or indwelling catheterisation found it reduced incidence of symptomatic UTI but possible harms were not assessed [128]. A multicentre RCT from the UK reported that prophylaxis was well-tolerated but development of antibiotic resistance was a concern [129].

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4.1.4.1.3.1 Summary of evidence and recommendations for urinary containment Summary of evidence Pads are effective in containing urine. Antibiotic prophylaxis may help reduce incidence of UTI in patients who self-catheterise or have an indwelling catheter, but at the cost of increasing antimicrobial resistance.

Recommendations Ensure that women with overactive bladder (OAB) and/or their carers are informed regarding available treatment options before deciding on urinary containment alone. Offer incontinence pads and/or containment devices for management of OAB-wet, either for temporary symptom control or where other treatments are not feasible. Offer prophylactic antibiotics to patients with recurrent urinary tract infections who perform clean intermittent self-catheterisation, or have an indwelling catheter, after discussion regarding the risk of increasing antimicrobial resistance.

LE 1b 1a

Strength rating Strong Strong Strong

4.1.4.1.4 Lifestyle interventions Examples of lifestyle factors that may be associated with UI include obesity, smoking, level of physical activity and liquid intake. Modification of these factors may improve symptoms of OAB. 4.1.4.1.4.1 Caffeine intake Many drinks contain caffeine, particularly coffee, tea and cola. Conflicting epidemiological evidence of urinary symptoms being aggravated by caffeine intake has focused attention on whether caffeine reduction may improve LUTS [130, 131]. A recent review of 14 interventional and 12 observational studies reported that reduction in caffeine intake may reduce symptoms of urgency, but the certainty of evidence was low with significant heterogeneity [132]. 4.1.4.1.4.2 Fluid intake Modification of fluid intake, particularly restriction, is a strategy commonly used by people with OAB to relieve symptoms. Advice on fluid intake given by healthcare professionals should be based on 24-hour fluid intake and urine output measurements. From a general health point of view, it should be advised that fluid intake should be sufficient to avoid thirst and that an abnormally low or high 24-hour urine output should be investigated. The few RCTs that have been published provide inconsistent evidence [133-135]. In most studies, the instructions for fluid intake were individualised and it is difficult to assess participant adherence to protocol. All available studies were in women. An RCT showed that a reduction in fluid intake by 25% improved symptoms in patients with OAB but not UI [135]. Personalised fluid advice compared to generic advice made no difference to continence outcomes in people receiving anticholinergics for OAB, according to an RCT comparing drug therapy alone to drug therapy with behavioural advice [136]. Patients should be warned of the possibility of worsening constipation as a consequence of fluid restriction. 4.1.4.1.4.3 Obesity and weight loss Being overweight or obese has been identified as a risk factor for LUTS in many epidemiological studies [137, 138]. There is evidence that the prevalence of both UUI and SUI increases proportionately with rising body mass index (BMI) [139]. However, the evidence base largely relates to obesity and SUI rather than UUI and OAB. Therefore, no definite inference can be drawn between obesity and the prevalence of OAB. 4.1.4.1.4.4 Smoking Smoking cessation is a generalised public health measure and has been shown to be weakly associated with improving urgency, frequency and UI [140, 141]. The effect of smoking cessation on LUTS was described as uncertain in a health technology assessment (HTA) review [142].

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4.1.4.1.4.5 Summary of evidence and recommendations for lifestyle interventions Summary of evidence Reduction of caffeine intake may reduce symptoms of frequency and urgency. Addition of personalised fluid intake advice to pharmacotherapy provided no additional benefit in patients with OAB. Reduction in fluid intake by 25% may help improve symptoms of OAB but not UI. Obesity is a risk factor for UI in women, but the relationship to other OAB symptoms remains unclear. There is weak evidence that smoking cessation will improve the symptoms of OAB. Recommendations Encourage overweight and obese adults with overactive bladder (OAB)/urinary incontinence to lose weight and maintain weight loss. Advise adults with OAB that reducing caffeine intake may improve symptoms of urgency and frequency, but not incontinence. Review type and amount of fluid intake in patients with OAB. Provide smoking cessation strategies to patients with OAB who smoke.

LE 2 2 1b 1b 3

Strength rating Strong Strong Weak Strong

4.1.4.1.5 Behavioural and physical therapies Terminology relating to behavioural and physical therapies remains confusing because of the wide variety of ways in which treatment regimens and combinations of treatments have been delivered in different studies [143]. The terms are used to encompass all treatments which require a form of self-motivated personal retraining by the patient and also include techniques which are used to augment this effect. Approaches include bladder training (BT) and PFMT, but terms such as bladder drill, bladder discipline, bladder re-education and behaviour modification are also used. Almost always in clinical practice, these will be introduced as part of a package of care including lifestyle changes, patient education and possibly some cognitive therapy as well. The extent to which individual therapists motivate, supervise and monitor these interventions is likely to vary but it is recognised that these influences are important components of the whole treatment package. 4.1.4.1.5.1 Prompted voiding and timed voiding The term ‘prompted voiding’ implies that carers, rather than the patient, initiate the patient going to void with the aim of preventing or reducing UI. This applies largely to an assisted care setting. Two systematic reviews (nine RCTs) [144, 145] confirmed a positive effect on continence outcomes for prompted voiding in comparison to standard care [145]. Timed voiding is defined as fixed, pre-determined, time intervals between toileting, applicable for those with or without cognitive impairment. A Cochrane review of timed voiding reviewed two RCTs, finding inconsistent improvement in continence compared with standard care in cognitively impaired adults [146]. 4.1.4.1.5.2 Bladder Training Bladder training (BT) is a programme of patient education along with a scheduled voiding regimen with gradually increasing voiding intervals. Specific goals are to correct faulty habit patterns of frequent urination, improve control over bladder urgency, prolong voiding intervals, increase bladder capacity, reduce incontinent episodes and restore patient confidence in controlling bladder function. The ideal form or intensity of a BT programme for OAB/UI is unclear. It is also unclear whether or not BT can prevent the development of OAB/UI. There have been three systematic reviews on the effect of BT compared to standard care confirming that BT is more effective than no treatment in improving UUI [67, 142, 147]. The addition of BT to anticholinergic therapy did not improve UUI compared to anticholinergics alone but it did improve frequency and nocturia [148]. This review identified seven RCTs in which BT was compared to drug therapy alone and only showed a benefit for oxybutynin in cure and improvement of UUI [148]. 4.1.4.1.5.3 Pelvic floor muscle training An immediate effect of contracting the PFMs is a simultaneous inhibition of urgency, detrusor contraction and incontinence [149]. Intensive and regular strength training of the PFMs over time increases PFM strength and endurance, and changes the morphology of the pelvic floor which may yield a more effective inhibition of the

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detrusor and help to stabilize the proximal urethra and improve urethral function. To date, there is a lack of basic and mechanistic studies to confirm that change of pelvic floor morphology improves OAB symptoms. A systematic review of 11 RCTs [150] including women with OAB compared the efficacy of PFMT vs. inactive control, usual care, other lifestyle modification or other intervention. The descriptive analysis revealed that PFMT significantly reduced OAB symptoms (frequency and UUI) in five RCTs, while the remaining six reported no significant difference. Significant heterogeneity in protocols precluded meaningful comparisons. 4.1.4.1.5.4 Electrical stimulation The details and methods of delivery of electrical stimulation (ES) vary considerably. Electrical stimulation of the pelvic floor can also be combined with other forms of conservative therapy, e.g. PFMT with and without biofeedback. Electrical stimulation is often used to assist women who cannot initiate contractions to identify their PFMs and in patients with OAB and UUI with the aim of inhibiting detrusor contraction. There is, however, lack of basic and mechanistic studies to confirm this theory. A systematic review has been done on 51 trials on 3,443 adults with OAB symptoms [151], with quality of evidence ranging from very low to moderate. Moderate quality evidence suggests ES is more likely to improve OAB symptoms compared to sham control, no treatment or placebo. Moderate quality evidence also suggested that ES was more likely to improve OAB symptoms compared to anticholinergic therapy. There was insufficient evidence for comparisons to PFMT and between different types of ES. 4.1.4.1.5.5 Acupuncture In a systematic review with meta-analysis of 10 RCTs including 794 patients (590 women), the authors reported that acupuncture might have an effect in reducing OAB symptoms compared to sham treatment [152]. The studies were of low quality and compared electro-acupuncture (EA) vs. sham acupuncture, or EA plus tolterodine vs. tolterodine alone. 4.1.4.1.5.6 Posterior tibial nerve stimulation Electrical stimulation of the posterior tibial nerve (PTNS) delivers electrical stimuli to the sacral micturition centre via the S2–S4 sacral nerve plexus. Stimulation is percutaneous with a fine (34-G) needle, inserted just above the medial aspect of the ankle (P-PTNS). Transcutaneous stimulation is also available (T-PTNS) that delivers stimulation via surface electrodes which do not penetrate skin. Treatment cycles typically consist of twelve weekly treatments of 30 minutes. 4.1.4.1.5.6.1 Percutaneous posterior tibial nerve stimulation The reviewed studies included two 12-week RCTs of P-PTNS against sham treatment [153, 154], one comparing PTNS to tolterodine, and a 3-year extension trial utilising a maintenance protocol in patients with UUI [155, 156]. The results of studies of PTNS in women with refractory UUI are consistent. Considered together, these results suggest that PTNS improves UUI in women who did not have adequate improvement or could not tolerate anti-muscarinic therapy. However, there is no evidence that PTNS cures UUI in women. In addition, PTNS is no more effective than tolterodine for improvement of UUI in women overall. 4.1.4.1.5.6.2 Transcutaneous posterior tibial nerve stimulation A small RCT compared transcutaneous PTNS plus standard treatment (PFMT and BT) with PFMT and BT alone in older women [157]. Women in the T-TPNS group were more likely to achieve improvement at the end of therapy. A systematic review of 13 trials (10 RCTs and 3 cohort studies) compared the efficacy of T-PTNS (treatment period between 4 and 12 weeks) with sham treatment, anticholinergics, and exercise in treatment of adults with OAB symptoms [158]. Of note, the populations were adult women and men, and some studies included patients with neurogenic OAB. Meta-analysis was possible in 2 RCTs comparing T-PTNS with sham treatment, and revealed mean reduction in total ICIQ-UI SF associated with T-PTNS of −3.79 points. 4.1.4.1.5.7 Summary of evidence and recommendations for behavioural and physical therapies Summary of evidence Bladder training is effective for improvement of UUI in women. The combination of BT with anticholinergic drugs does not result in greater improvement of UUI, but may improve frequency and nocturia.

24

LE 1b 1b

MANAGEMENT OF NON-NEUROGENIC FEMALE LOWER URINARY TRACT SYMPTOMS (LUTS) - 2021

Prompted voiding, either alone or as part of a behavioural modification programme, improves continence in elderly, care-dependent people. Pelvic floor muscle training may improve symptoms of frequency and incontinence in women. Electrical stimulation may improve symptoms of OAB in some women, but the type and mode of delivery of ES remains variable and poorly standardised. Percutaneous posterior tibial nerve stimulation appears effective for improvement of UUI in women who have had no benefit from anticholinergic medication. A maintenance programme of P-PTNS has been shown to be effective up to three years. Percutaneous-PTNS has comparable effectiveness to tolterodine for improvement of UUI in women. No serious adverse events have been reported for P-PTNS in UUI. Transcutaneous-PTNS appears to be effective in reducing OAB symptoms compared to sham treatment. Recommendations Offer prompted voiding for adults with overactive bladder (OAB) who are cognitively impaired. Offer bladder training as a first-line therapy to adults with OAB/urgency urinary incontinence (UUI). Ensure that pelvic floor muscle training programmes are as intensive as possible. Consider posterior tibial nerve stimulation as an option for improvement of OAB/UUI in women who have not benefited from anticholinergic medication.

1b 1b 1a 2b 1b 1b 3 1a

Strength rating Strong Strong Strong Strong

4.1.4.2 Pharmacological management 4.1.4.2.1 Anticholinergic drugs Anticholinergic (antimuscarinic) drugs are currently the mainstay of treatment for OAB. They differ in their pharmacological profiles, e.g. muscarinic receptor affinity and other modes of action and in their pharmacokinetic properties, e.g. lipid solubility and half-life. The evaluation of cure or improvement of OAB is made harder by the lack of standard definitions. In general, systematic reviews note that the overall treatment effect of drugs is usually small but larger than placebo. In addition, some RCTs have UI as an outcome rather than UUI. Dry mouth is the commonest side effect, though constipation, blurred vision, fatigue and cognitive dysfunction may occur with anticholinergic drugs [147]. Immediate-release (IR) anticholinergic preparations provide maximum dosage flexibility, including an off-label ‘on-demand’ use. Immediate-release drugs have a greater risk of side effects than extended release (ER) formulations because of differing pharmacokinetics. A transdermal delivery system (TDS) and gel developed for oxybutynin gives a further alternative formulation. Seven systematic reviews of individual anticholinergic drugs vs. placebo were reviewed [147, 159-164]. Most studies included patients with a mean age of 55–60 years. The evidence reviewed was consistent, indicating that ER and IR formulations of anticholinergics offer clinically significant short-term improvement rates for OAB compared to placebo. On balance, IR formulations tend to be associated with more side effects compared to ER formulations [163]. A network meta-analysis of 128 RCTs comparing anticholinergics with placebo or with other anticholinergics revealed that all anticholinergics, except imidafenacin, showed significant cure or improvement in OAB symptoms in women and men [165]. Cure of UUI was deemed to be the most important outcome measure. Table 1 shows a summary of the findings from systematic reviews [147]. In summary, every drug where cure outcomes for UUI were available showed superiority compared to placebo, but the absolute size of effect was small. There is limited evidence that patients who do not respond to a first-line anticholinergic treatment may respond to a higher dose or a different anticholinergic agent [166, 167]. Risk of adverse events was often represented by trial-withdrawal because of adverse events, although this does not reflect clinical practice. The cure rates for darifenacin were not included in the United States (U.S.) Agency for Healthcare Research and Quality (AHRQ) review. Continence rates were 29–33% for darifenacin compared to 17–18% for placebo [147]. Transdermal oxybutynin has shown a significant improvement in the number of incontinence episodes and micturitions per day vs. placebo and other oral formulations but cure of incontinence was not reported as an outcome [147].

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Oxybutynin topical gel was superior to placebo for improvement of UUI with a higher proportion of participants being cured [147, 168]. Table 1: S  ummary of cure rates and discontinuation rates of anticholinergic drugs from RCTs which reported these outcomes [147] Drug

No. of studies

Cure of incontinence Fesoterodine 2 Oxybutynin (includes IR) 4 Propiverine (includes IR) 2 Solifenacin 5 Tolterodine (includes IR) 4 Trospium (includes IR) 4 Discontinuation due to adverse events

Darifenacin Fesoterodine Oxybutynin (includes IR) Propiverine (includes IR) Solifenacin Tolterodine (includes IR) Trospium (includes IR)

7 4 5 2 7 10 6

n

RR (95% CI) (of curing UI)

NNT (95% CI) (to achieve one cure of UI)

2,465 992 691 6,304 3,404 2,677

1.3 (1.1–1.5) 1.7 (1.3–2.1) 1.4 (1.2–1.7) 1.5 (1.4–1.6) 1.2 (1.1–1.4) 1.7 (1.5–2.0)

8 (5–17) 9 (6–16) 6 (4–12) 9 (6–17) 12 (8–25) 9 (7–12) NNT (95% CI) (for one discontinuation)

3,138 4,433 1,483 1,401 9,080 4,466 3,936

RR (95% CI) (of discontinuation) 1.2 (0.8–1.8) 2.0 (1.3–3.1) 1.7 (1.1–2.5) 2.6 (1.4–5) 1.3 (1.1–1.7) 1.0 (0.6–1.7) 1.5 (1.1–1.9)

33 (18–102) 16 (8–86) 29 (16–77) 78 (39–823) 56 (30–228)

CI = confidence interval; IR = immediate release; n = number of patients; NNT = number to treat; UI = urinary incontinence; RR = relative risk. 4.1.4.2.1.1 Comparison of different anticholinergic agents Head-to-head comparison trials of the efficacy and side effects of different anticholinergic agents are of interest for decision making in practice. A network meta-analysis revealed no clear best anticholinergic preparation for cure or improvement [165]. Darifenacin (40%), tolterodine IR and oxybutynin ER (13% each) appeared to score highest in indirect comparisons. Fesoterodine and oxybutynin IR were more effective than both oxybutynin (transdermal) and tolterodine ER. There were no clinically significant differences between anticholinergics for voiding and UI outcomes. Another network meta-analysis of 53 RCTs compared the efficacy and tolerability of solifenacin 5 mg with other oral anticholinergics in the treatment of adults with OAB symptoms [169]. The analysis revealed that solifenacin 5 mg/day was significantly more effective than tolterodine 4 mg/day for reducing UUI episodes, but significantly less effective than solifenacin 10 mg/day for micturition episodes. Solifenacin 5 mg/day showed significantly lower risk of dry mouth compared with other anticholinergics. There were no significant differences for risk of blurred vision or constipation. It is notable that nearly all the primary studies in this category were industry-sponsored. Upward dose titration is often included in the protocol for the experimental arm, but not for the comparator arm. In general, these studies have been designed to achieve regulatory approval. They have short treatment durations (twelve weeks) and a primary outcome of a change in OAB symptoms rather than a cure of, or an improvement in, UUI, which were generally analysed as secondary outcomes. The clinical utility of these trials in real life practice is debatable. Most trials were of low or moderate quality [161]. The 2012 AHRQ review included a specific section addressing comparisons of anticholinergic drugs (Table 1). No single anticholinergic agent improved QoL more than another [161]. Dry mouth is the most prevalent adverse effect. Good evidence indicates that, in general, higher doses of any drug are likely to be associated with higher rates of adverse events. Also, ER formulations of short-acting drugs and longer-acting drugs are generally associated with lower rates of dry mouth than IR preparations [161, 170]. Oxybutynin IR showed higher rates of dry mouth than tolterodine IR and trospium IR, but lower rates of dry mouth than darifenacin,

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15 mg daily [161, 170]. Overall, oxybutynin ER has higher rates of dry mouth than tolterodine ER, although the incidence of moderate or severe dry mouth were similar. Transdermal oxybutynin had a lower rate of dry mouth than oxybutynin IR and tolterodine ER, but had an overall higher rate of withdrawal due to adverse skin reactions [161]. Solifenacin 10 mg daily, had higher rates of dry mouth than tolterodine ER [161]. Fesoterodine 8 mg daily, had a higher rate of dry mouth than tolterodine 4 mg daily [171-173]. In general, similar discontinuation rates were observed, irrespective of differences in the occurrence of dry mouth (doses have been given where the evidence relates to a specific dose level typically from trials with a dose escalation element). 4.1.4.2.1.2 Anticholinergic drugs versus conservative treatment The choice of drug vs. conservative treatment of OAB patients is an important question. More than 100 RCTs and high-quality reviews are available [148, 161, 162, 174-176]. Most of these were independent studies. A U.S. HTA [174] found that trials were of a low- or moderate-quality. The main focus of the review was to compare the different drugs used to treat UUI. In one study, multi-component behavioural modification produced significantly greater reductions in incontinence episodes compared to oxybutynin and higher patient satisfaction for behavioural vs. drug treatment. The combination of BT and solifenacin in female patients with OAB conferred no additional benefit in terms of continence vs. solifenacin monotherapy [177]. A recent Cochrane review on the benefit of adding PFMT to other active treatments of UI in women showed insufficient evidence of any benefit in adding PFMT to drug treatment [178]. One RCT reported a similar improvement in subjective parameters with either transcutaneous electrical nerve stimulation (T-PTNS) or oxybutynin [179]. One study compared tolterodine ER to transvaginal/anal ES in female patients with OAB symptoms and/or UUI without differences in UI outcomes [180]. 4.1.4.2.1.3 Anticholinergic drugs: adherence and persistence Most studies on anticholinergic medication are short term (twelve weeks). Adherence in clinical trials is considered to be much higher than in clinical practice [181]. This topic has been reviewed for the development of a previous version of these Guidelines [182]. Two open-label extensions of RCTs of fesoterodine 8 mg showed adherence rates at two years of 49–84% [183, 184]. The main drugs studied were oxybutynin and tolterodine IR and ER. Non-persistence rates were high for tolterodine at twelve months, and particularly high (68–95%) for oxybutynin. Five articles reported ‘median days to discontinuation’, but follow-up periods varied from < 30 days up to 50 days [185-189]. In a military health system where free medication was provided, the median time to discontinuation extended to 273 days [186]. Data on adherence/persistence from open-label extension populations are questionable as it could be argued that these patients are self-selected on the basis of their compliance. A Longitudinal Disease Analyser database study has indicated an increasing discontinuation rate, following treatment with anticholinergics, from 74.8% at one year to 87% at three years [190]. Several of the RCTs tried to identify the factors associated with low/lower adherence or persistence of anticholinergics. These were identified as: • low level of efficacy (41.3%); • adverse events (22.4%); • cost (18.7%), although higher adherence rates were observed when drugs were provided at no cost to the patient [186]. Other reasons for poor adherence included: • IR vs. ER formulations; • age (lower persistence among younger adults); • unrealistic expectations of treatment; • gender distribution (better adherence/persistence in female patients); • ethnic group (African-Americans and other ethnic minorities are more likely to discontinue or switch treatment).

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4.1.4.2.1.4 Summary of evidence and recommendations for anticholinergic drugs Summary of evidence No anticholinergic drug is clearly superior to another for cure or improvement of OAB/UUI. Higher doses of anticholinergic drugs are more effective to improve OAB symptoms, but exhibit a higher risk of side effects. Once daily (extended release) formulations are associated with lower rates of adverse events compared to immediate release preparations, although similar discontinuation rates are reported in clinical trials. Dose escalation of anticholinergic drugs may be appropriate in selected patients to improve treatment effect although higher rates of adverse events can be expected. Transdermal oxybutynin (patch) is associated with lower rates of dry mouth than oral anticholinergic drugs, but has a high rate of withdrawal due to skin reaction. There is no consistent evidence to show superiority of drug therapy over conservative therapy for treatment of OAB. Behavioural treatment may have higher patient satisfaction rates than drug treatment. There is insufficient evidence as to the benefit of adding PFMT to drug treatment for OAB. Adherence to anticholinergic treatment is low and decreases over time because of lack of efficacy, adverse events and/or cost. Most patients will stop anticholinergic agents within the first three months. Recommendations Offer anticholineric drugs to adults with overactive bladder (OAB) who fail conservative treatment. Consider extended release formulations of anticholinergic drugs, whenever possible. If an anticholinergic treatment proves ineffective, consider dose escalation or offering an alternative anticholinergic formulation, or mirabegron, or a combination. Encourage early review (of efficacy and side effects) of patients on anticholinergic medication for OAB.

LE 1a 1a 1b 1b 1b 1b 1b 1b 2a 2a

Strength rating Strong Strong Strong Strong

4.1.4.2.2 Beta-3 agonists Mirabegron was the first clinically available beta-3 agonist. Beta-3 adrenoceptors are the predominant beta receptors expressed on the smooth muscle cells of the detrusor and their stimulation is thought to induce detrusor relaxation. Vibegron is another beta-3 agonist commercially available in some countries. Mirabegron has undergone evaluation in industry-sponsored phase II and phase III trials [191-194]. Three systematic reviews assessing the clinical effectiveness of mirabegron [191, 192, 195] reported that mirabegron at doses of 25, 50 and 100 mg, results in significantly greater reduction in UI episodes, urgency episodes and micturition frequency than placebo, with no difference in the rate of common adverse events [192]. The dry rates in most of these trials are between 35–40% for placebo, and between 43 and 50% for mirabegron. In all trials the statistically significant difference is consistent only for improvement but not for cure of UI. Similar improvements in frequency of UI episodes and micturitions/24 hours was found whether or not patients had previously tried anticholinergic agents. One systematic review showed that mirabegron is similarly efficacious as most anticholinergics in reducing UUI episodes [196]. The most common treatment adverse events in the mirabegron groups were hypertension (7.3%), nasopharyngitis (3.4%) and UTI (3%), with the overall rate similar to placebo [191, 194, 197]. In a twelve-month, active-controlled RCT of mirabegron 50/100 mg vs. tolterodine ER 4 mg, the improvement in efficacy seen at twelve weeks was sustained at 12-month evaluation in all groups. The reported dry rates at twelve months were 43%, 45% and 45% for mirabegron 50 mg, 100 mg and tolterodine 4 mg respectively [197]. Post-hoc analyses of RCTs showed that clinical improvement observed in parameters of OAB severity translates into an improvement in HRQoL and efficacy is maintained in patients with more severe degree of UI [198, 199]. No risk of QTc prolongation on electrocardiogram [200] and no raised intraocular pressure [201] were observed up to the 100 mg dose; however, patients with uncontrolled hypertension or cardiac arrhythmia were excluded from these trials. There is no significant difference in rate of side effects at different doses of mirabegron [197]. Patients on certain concurrent medications (e.g. metoprolol) should be counselled that, due to common metabolism pathways, their medication dosage may need to be adjusted. In the case of patients taking

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metoprolol, blood pressure should be monitored after starting mirabegron and, if necessary, the metoprolol dosing may need to be changed. Equivalent adherence was observed for tolterodine and mirabegron at twelve months (5.5% and 3.6%), although the incidence of dry mouth was significantly higher in the tolterodine group [197]. In mirabegron treated patients, improvement in objective outcome measures correlates directly with clinically relevant PROMs (Overactive Bladder questionnaire [OAB-q] and Patient Perception of Bladder Condition [PPBC]) [198, 202]. Data from a large Canadian Private Drug Plan database suggest a higher adherence rate for mirabegron compared to anticholinergics [203]. An RCT in patients who had inadequate response to solifenacin monotherapy 5 mg, demonstrated that combination treatment with mirabegron 50 mg had a higher chance of achieving clinically meaningful improvement in UI as compared to dose escalation of solifenacin [204]. 4.1.4.2.2.1 Summary of evidence and recommendation for mirabegron Summary of evidence Mirabegron is better than placebo and as efficacious as anticholinergics for improvement of OAB/UUI symptoms. Adverse event rates with mirabegron are similar to placebo. Patients inadequately treated with solifenacin 5 mg may benefit more from the addition of mirabegron than dose escalation of solifenacin.

Recommendation Offer mirabegron as an alternative to anticholinergics to women with overactive bladder who fail conservative treatment.

LE 1a 1a 1b

Strength rating Strong

4.1.4.2.3 Anticholinergics and beta-3 agonists: the elderly and cognition Trials have been conducted in elderly people with OAB. Considerations in this patient group include the multifactorial aetiology of OAB in the elderly, comorbidities such as cognitive impairment, the effect of co-medications and the risk of adverse events. The effects of anticholinergic agents on cognition have been studied in more detail. Systematic reviews have included sections on the efficacy and safety of anticholinergics in elderly patients [147, 161]. A 2012 systematic review found inconclusive evidence as to the impact of anticholinergics on cognition [205]. Two recent longitudinal cohort studies in patients using drugs with anticholinergic effect showed a deterioration in cognitive function, alteration in CNS metabolism and an association with brain atrophy [206, 207]. In general, the long-term impact of anticholinergic agents specifically approved for OAB treatment on specific patient cohorts is poorly understood [208-211]. •

Oxybutynin: There is evidence that oxybutynin IR may cause/worsen cognitive dysfunction in adults [208, 210, 212, 213]. One RCT with oxybutynin topical gel focused on cognitive and psychomotor function after one week of treatment showed no clinical meaningful effect on recent memory or other cognitive functions in healthy old adults [213]. Another retrospective study did not show cognitive impairment after 4 weeks of treatment with transdermal oxybutynin [210]. Recent evidence has emerged from a prospective cohort study showing cumulative cognitive deterioration associated with prolonged use of anticholinergic medication including oxybutynin [206]. More rapid functional deterioration might result from the combined use of cholinesterase inhibitors and anticholinergic agents in elderly patients with cognitive dysfunction [214].

•

Solifenacin: One pooled analysis [215] has shown that solifenacin does not increase cognitive impairment in the elderly. No age-related differences in the pharmacokinetics of solifenacin in different age groups was found, although more frequent adverse events in subjects over 80 years of age were observed. No cognitive effect on healthy elderly volunteers was shown [216]. In a sub-analysis of a large trial, solifenacin 5–10 mg improved symptoms and QoL in people ≥ 75 years who had not responded to tolterodine [217]. In patients with mild cognitive impairment, ≥ 65 years, solifenacin showed no difference in efficacy between age groups and a lower incidence of most side effects compared to oxybutynin IR [213, 218].

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•

Tolterodine: No change in efficacy or side effects related to age has been reported, although a higher discontinuation rate was found for both tolterodine and placebo in elderly patients [208]. Two RCTs in the elderly found a similar efficacy and side effect profile to younger patients [219-222]. Post-hoc analysis has shown little effect on cognition. One non-randomised comparison showed lower rates of depression in elderly participants treated with tolterodine ER compared to oxybutynin IR [223].

•

Darifenacin: Two RCTs in the elderly population (one in patients with UUI and the other in volunteers) concluded that darifenacin was effective with no risk of cognitive change, measured as memory scanning tests, compared to placebo [224, 225]. Another study on darifenacin and oxybutynin ER in elderly subjects concluded that the two agents had a similar efficacy, but that cognitive function was more often affected in the oxybutynin ER arm [210].

•

Trospium chloride: Trospium does not appear to cross the blood brain barrier in healthy individuals due to its molecular characteristics (quaternary amine structure and hydrophilic properties). Two studies in healthy volunteers using electro-encephalography (EEG) showed no effect from trospium whilst tolterodine caused occasional changes and oxybutynin caused consistent changes [226, 227]. No evidence as to the comparative efficacy and side effect profiles of trospium in different age groups is available. However, there is some evidence that trospium does not impair cognitive function [211, 228] and that it is effective compared to placebo in the elderly [229].

•

Fesoterodine: Pooled analyses of the RCTs of fesoterodine confirmed the efficacy of the 8 mg but not the 4 mg dose in over 75-year olds [183]. Adherence was lower in the over-75-year-old group but the effect on mental status was not reported [173, 183, 230]. A more recent RCT showed efficacy of fesoterodine in the vulnerable elderly with no differences in cognitive function at twelve weeks [231].

•

Mirabegron: Analysis of pooled data from three RCTs showed efficacy and safety of mirabegron in elderly patients [232].

4.1.4.2.3.1 Applicability of evidence to the general elderly population It is not clear how much the data from pooled analyses and subgroup analyses from large RCTs can be extrapolated to a general ageing population. Community-based studies of the prevalence of anticholinergic side effects may be the most helpful [233]. When starting anticholinergics in elderly patients, mental function should be assessed objectively and monitored [234]. No consensus exists as to the best mental function test to detect changes in cognition [214, 235]. 4.1.4.2.3.2 Anticholinergic burden A number of medications have anticholinergic effects and if another anticholinergic drug is added the possible greater cumulative effects on cognition should be considered. Lists of drugs with anticholinergic properties are available from several sources [236]. No studies were identified specifically in older people with LUTS, but evidence was available from observational cohort studies relating to the risk in a general population of older people. Two systematic reviews of largely retrospective cohort studies showed a consistent association between longterm anticholinergic use and cognitive dysfunction [237, 238]. Longitudinal studies in older people over 2−4 years have found increased rates of decline in cognitive function for patients on anticholinergics or drugs with anticholinergic effects [206, 207, 239, 240]. It is unclear whether there is a direct correlation between cognitive dysfunction caused by medication and the long-term risk of the development of dementia. 4.1.4.2.3.3 Summary of evidence and additional recommendations for use of anticholinergic drugs in the elderly Summary of evidence Anticholinergic drugs are effective in elderly patients suffering from OAB/UUI. Mirabegron has been shown to be efficacious and safe in elderly women suffering from OAB. In older women the cognitive impact of drugs which have anticholinergic effects is cumulative and increases with length of exposure. Oxybutynin may worsen cognitive function in elderly women. Darifenacin, fesoterodine, solifenacin and trospium have not been shown to cause cognitive dysfunction in elderly women in short-term studies.

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LE 1b 1b 2 2 1b

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Recommendations Strength rating Long-term anticholinergic treatment should be used with caution in elderly women, especially Strong those who are at risk of, or have pre-existing cognitive dysfunction. Assess anticholinergic burden and associated co-morbidities in patients being considered Weak for anticholinergic therapy for overactive bladder syndrome. 4.1.4.2.4 Oestrogens Oestrogenic drugs including conjugated equine oestrogens, oestradiol, tibolone and raloxifene, are used as hormone replacement therapy (HRT) for women with natural or therapeutic menopause. Oestrogen treatment for UI has been tested using oral, transdermal and vaginal routes of administration. Vaginal (local) treatment is primarily used to treat symptoms of vaginal atrophy in post-menopausal women. Available evidence related mainly to SUI and although some reviews include participants with UUI, it is difficult to generalise the results to women with predominantly OAB/UUI. The association of LUTS with Genitourinary Syndrome of Menopause (GSM) should be considered [241]. GSM is a relatively new term that describes various menopausal symptoms and signs associated with physical changes of the vulva, vagina, and LUT. These include mucosal pallor/erythema, loss of vaginal rugae, tissue fragility/fissures, vaginal petechiae, urethral mucosal prolapse, introital retraction and vaginal dryness. There is evidence from a systematic review to suggest benefit from vaginal oestrogen therapy in GSM [242]. All vaginal oestrogens demonstrated superiority in objective endpoints and subjective endpoints of GSM compared to placebo. Only some trials demonstrated superiority vs. placebo in urogenital symptoms (UI, recurrent UTI, urgency, frequency). No significant difference was observed between various dosages and dosage forms of vaginal oestrogen products. Vaginal oestrogen showed superiority over vaginal lubricants and moisturizers for the improvement of objective clinical endpoints of vulvovaginal atrophy but not for subjective endpoints [242]. Available evidence suggests that vaginal oestrogen treatment with oestradiol and oestriol is not associated with the increased risk of thromboembolism, endometrial hypertrophy, and breast cancer seen with systemic administration [243-245]. 4.1.4.2.4.1 Summary of evidence and recommendation for oestrogen therapy Summary of evidence Vaginal oestrogen therapy may improve symptoms associated with GSM, of which OAB may be a component.

Recommendation Offer vaginal oestrogen therapy to women with lower urinary tract symptoms and associated symptoms of genito-urinary syndrome of menopause.

LE 1a

Strength rating Weak

4.1.4.3 Surgical management 4.1.4.3.1 Bladder wall injection of botulinum toxin A Onabotulinum toxin A (onabotA; BOTOX®) 100 U is licenced in Europe to treat OAB with persistent or refractory UUI in adults of both genders [246, 247]. Surgeons should be aware that other doses of onabotA and other formulations of botulinum toxin A, abobotulinum toxin A and incobotulinum toxin A, are not licensed for use in OAB/UUI. Doses for onabotA are not transposable to the other brands of botulinum toxin A. The continued efficacy of repeat injections is usual, but discontinuation rates may be high [248, 249]. The most important adverse events related to onabotA 100U injection detected in the regulatory trials were UTI and an increase in PVR that may require CISC [250]. Following a dose ranging study in which the 100 U of onabotA was established as the ideal dose, a phase III trial randomised (1:1) the same group of 557 OAB-wet patients whose symptoms were not adequately managed with anticholinergics to receive bladder wall injections of onabotA (100 U) or saline. At baseline, the population had on average more than five episodes of UUI, around twelve micturitions per day and a small PVR. At week twelve, in patients treated with onabotA, UUI episodes/day were halved and the number of micturitions/day reduced by more than two. A total of 22.9% of the patients in the onabotA arm were fully dry, against 6.5% in the saline arm [250]. Rates of urinary retention are not reported in systematic reviews, and a Cochrane review reported no significant difference in PVR between the onabotA and placebo groups [251].

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Quality of life was substantially improved in the onabotA arm, as shown by the > 2.5 times improvement in I-QOL scores compared to baseline. Cohort studies have shown the effectiveness of bladder wall injections of onabotA in the elderly and frail elderly [252], though the success rate might be lower and the PVR (> 150 mL) higher in this group. The median time to request re-treatment in the pooled analysis of the two RCTs was 24 weeks [247, 250]. Follow-up over 3.5 years showed consistent or increasing duration of effect for each subsequent treatment, with a median of 7.5 months. Considerable differences between patients have been observed on secondary analysis [253]. A recent RCT compared onabotA injection 100 U to solifenacin (with dose escalation or switch to trospium possible in the solifenacin group) and showed similar rates of improvement in UUI over the course of six months [254]. However, patients receiving onabotA were not only more likely to have cure of UUI (27% vs. 13%, p = 0.003), but also had higher rates of urinary retention during the initial two months (5% vs. 0%) and of UTIs (33% vs. 13%). Patients taking anticholinergics were more likely to have dry mouth. These results are further strengthened by a 2017 systematic review and network meta-analysis of onabotulinum toxin A vs. oral therapies (anticholinergics and mirabegron) for OAB at 12 weeks [255]. This review reported that patients receiving onabotulinum toxin had the greatest reduction in UUI episodes, urgency episodes, micturition frequency and the highest odds of achieving dryness as well as ≥ 50% reduction from baseline UI episodes/ day (type not specified). However, adverse events were not reported in this network meta-analysis. Identification of DO in urodynamics does not appear to influence the outcome of onabotulinum toxin A injections in patients with UUI [85]. 4.1.4.3.1.1 Summary of evidence and recommendations for bladder wall injection of botulinum toxin A Summary of evidence A single treatment session of onabotulinum toxin A (100 U) injected in the bladder wall is more effective than placebo at curing and improving UUI/OAB symptoms and QoL. There is no evidence that repeated injections of onabotulinum toxin A have reduced efficacy but discontinuation rates are high. There is a risk of increased PVR and UTI with onabotulinum toxin A injections. The risk of bacteriuria after onabotulinum toxin A (100 U) injection is high but the clinical significance of this remains uncertain. Onabotulinum toxin A (100 U) is superior to anticholinergics and mirabegron for cure of UUI and improvement of symptoms of OAB at twelve weeks.

LE 1a 2a 2 1b 1a

Recommendations Strength rating Strong Offer bladder wall injections of onabotulinum toxin A (100 U) to patients with overactive bladder/urgency urinary incontinence refractory to conservative therapy (such as pelvic floor muscle training and/or drug treatment). Strong Warn patients of the limited duration of response, risk of urinary tract infection and the possible prolonged need for clean intermittent self-catheterisation (ensure that they are willing and able to do so). 4.1.4.3.2 Sacral nerve stimulation Sacral nerve stimulation involves placing electrodes adjacent to the sacral nerve roots and delivering an electric current to the area via an attached battery implanted in the buttock which delivers low-amplitude stimulation resulting in modulation of neural activity and stabilisation of bladder electrical activity through a mechanism that is, as yet, not fully understood. In most centres, test stimulation with a temporary or permanent electrode will be performed to assess response, before undertaking permanent stimulator implantation. All randomised studies suffer from the limitation that patients cannot be blinded to the treatment allocation since all recruited subjects had to respond to a test phase before randomisation. A Cochrane review of the literature until March 2008 [256] identified three RCTs that investigated sacral nerve stimulation in patients with refractory UUI. The majority of included studies compared a strategy of immediate implantation vs. delayed implantation.

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One study compared implantation to controls who stayed on medical treatment and received delayed implantation at six months. Fifty percent of the immediately implanted group had > 90% improvement in UUI at six months compared to 1.6% of the control group [257]. The effect on generic QoL measured by the SF-36, was unclear as it differed between the groups in only one of the eight dimensions. The other RCT achieved similar results, although these patients had already been included in the first report [258]. The results of seventeen case series of patients with UUI, who were treated early with SNS, were reviewed [259]. After a follow-up duration of between one and three years, approximately 50% of patients with UUI demonstrated > 90% reduction in UI, 25% demonstrated 50–90% improvement, and another 25% demonstrated < 50% improvement. Two case series describing the outcome of SNS, with a mean or median follow-up of at least four years [260, 261] reported continued success (> 50% improvement of original symptoms) in patients available for follow-up. Cure rates for UUI were 15% [261]. A more recent RCT comparing a strategy of onabotulinum toxinA injection (200 IU), repeated as required, against a strategy of test and, if indicated, subsequent permanent SNS showed lower cure rates with SNS at six months: 20% in the onabotulinumtoxinA group and 4% in the SNS group had complete resolution of UUI (p < 0.001) [262]. Forty-six per cent in the onabotulinumtoxinA group and 26% in the SNS group had at least a 75% reduction in the number of episodes of UUI (p < 0.001). This 4% cure rate is also lower than the six month cure rate in another RCT of SNS vs. standard medical therapy which reported a 39% continence rate in the SNS group at six months; however, the mean (SD) baseline leaks per day (2.4 [± 1.7]) for the SNS group in this study were lower , reflecting a less severely affected population [263]. Two-year follow-up data from 87% of participants in this trial suggests no significant deterioration in treatment outcomes over two years, although satisfaction rates and treatment endorsement remain higher with onabotulinum toxin. Interestingly, the rates of complete resolution of UI (5% for both) as well as ≥ 75% reduction in UUI episodes (22% onabotulinum toxin vs. 21% SNM) were equivalent at the 2-year mark [264]. Sacral nerve stimulation revision and removal occurred in 3% and 9% of this cohort, respectively. Some of these differences in outcome could potentially be explained by performance bias particularly the difference in type of permanent lead used and potential learning curve effects within the SNS cohort as well as the use of a relatively high (200 U) dose of onabotulinum toxin A. A 2018 review of studies including SNS with at least 6 months follow-up reported dry rates of between 43 and 56% [265]. Adverse events occurred in 50% of implanted cases, with surgical revision necessary in 33–41% [261, 262]. In a sub-analysis of the RCT, the outcomes of UUI patients, with or without pre-implant DO, were compared. Similar success rates were found in patients with or without urodynamic DO [266]. 4.1.4.3.2.1 Summary of evidence and recommendation for sacral nerve stimulation Summary of evidence Sacral nerve stimulation is more effective than continuation of failed conservative treatment for OAB/ UUI, but no sham controls have been used. Sacral nerve stimulation is not more effective than onabotulinumA toxin 200 U injection at 24 months. In patients who have been implanted 50% improvement of UUI is maintained in at least 50% of patients and 15% may remain cured at four years. The use of tined, permanent electrodes in a staged approach results in more patients receiving the final implant than occurs with temporary test stimulation. Recommendation Offer sacral nerve stimulation to patients who have overactive bladder/urgency urinary incontinence refractory to anticholinergic therapy.

LE 1b 1b 3 4

Strength rating Strong

4.1.4.3.3 Cystoplasty/urinary diversion 4.1.4.3.3.1 Augmentation cystoplasty In augmentation cystoplasty (also known as clam cystoplasty), a detubularised segment of bowel is inserted into the bivalved bladder wall. The distal ileum is the bowel segment most often used but any bowel segment can be utilised if it has the appropriate mesenteric length. Most of the evidence pertaining to cystoplasty comes from patients with neuropathic bladder dysfunction. One study did not find any difference between bivalving the bladder in the sagittal or in the coronal plane [267, 268]. The procedure can be done, with equal success by open or robotic techniques, although the robotic consumes considerably more operative time [269].

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There are no RCTs comparing bladder augmentation to other treatments for patients with OAB/UUI. Most often, bladder augmentation is used to correct neurogenic DO, small capacity or low-compliant bladders caused by fibrosis, chronic infection such as tuberculosis, radiation or chronic inflammation from interstitial cystitis. The largest case series of bladder augmentation in a mixed population of idiopathic and neurogenic UUI included 51 women [270]. At an average follow-up of 74.5 months, only 53% were continent and satisfied with the surgery, whereas 25% had occasional leaks and 18% continued to have disabling UUI. It seems that the results for patients with idiopathic DO (58%) appeared to be less satisfactory than for patients with neurogenic UUI (90%). Malignant transformation was not reported in this series; however, it has been documented in other series and a systematic review [271-273]. Less than 60 cases have been reported worldwide, and almost all are exclusively beyond 10 years after the original cystoplasty surgery [274]. Adverse effects were common and have been summarised in a review over five to seventeen years of more than 267 cases, 61 of whom had non-neurogenic UUI [275]. In addition, many patients may require CISC to obtain adequate bladder emptying (Table 2). It is unclear if mucolytic agents will effectively reduce mucus accumulation. The only RCT that was identified comparing various mucolytic agents did not find significant benefits with the use of N-acetylcysteine, aspirin, or ranitidine. In one small study (n = 40), the use of subcutaneous octreotide immediately before, and for 15 days after surgery was reported to yield significant reductions in mucus production, the need for bladder irrigation to clear blockages, and the mean duration of hospital stay [276]. Before cystoplasty all potential complications should be outlined and both before and after surgery patients should be well supported by stoma/continence nurses. Depending on the relative costs of Onabotulinum Toxin A and augmentation cystoplasty, the latter can be cost effective within five years if the complication rate is low and duration of effect of Onabotulinum Toxin A < 5 months [277]. Table 2: Complications of bladder augmentation Short-term complications Bowel obstruction Infection Thromboembolism Bleeding Fistula Long-term complications Clean intermittent self-catheterisation Urinary tract infection/bacteriuria Urinary tract stones Metabolic disturbance Deterioration in renal function Bladder perforation Change in bowel symptoms

Affected patients (%) 2 1.5 1 0.75 0.4 Affected patients (%) 38 70% asymptomatic 20% symptomatic 13 16 2 0.75 25

4.1.4.3.3.2 Detrusor myectomy (bladder auto-augmentation) Detrusor myectomy aims to increase bladder capacity and reduce storage pressures by incising or excising a portion of the detrusor muscle, to create a bladder mucosal ‘bulge’ or pseudo-diverticulum. It was initially described as an alternative to bladder augmentation in children [278]. Two case series in adult patients with idiopathic and neurogenic bladder dysfunction, demonstrated poor longterm results caused by fibrosis of the pseudo-diverticulum [279, 280]. This technique is rarely, if ever, used nowadays. 4.1.4.3.3.3 Urinary diversion Urinary diversion remains a reconstructive option for patients with intractable UI after multiple pelvic procedures, radiotherapy or pelvic pathology leading to irreversible sphincteric incompetence or fistula formation. These patients may be offered irreversible urinary diversion surgery. Options include ileal conduit urinary diversion, orthotopic neobladder and heterotopic neobladder with Mitrofanoff continent catheterisable conduit. There is insufficient evidence to comment on which procedure leads to the most improved QoL.

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A small study comparing ileal with colonic conduits concluded that there were no differences in the relative risks of UUT infection and uretero-intestinal stenosis. However, there are no studies that have specifically examined these techniques in the treatment of intractable OAB/UUI [267]. Therefore, careful consideration on which operation is undertaken will depend on thorough pre-operative counselling, access to stoma/continence nurses as well as patient factors to allow for fully informed patient choice. 4.1.4.3.3.4 Summary of evidence and recommendations for cystoplasty/urinary diversion Summary of evidence There is limited evidence of the effectiveness of augmentation cystoplasty and urinary diversion in treatment of idiopathic OAB. Augmentation cystoplasty and urinary diversion are associated with high risks of short- and long-term severe complications. The need to perform CISC following augmentation cystoplasty is very common. There is no evidence comparing the efficacy or adverse effects of augmentation cystoplasty to urinary diversion. Detrusor myectomy is ineffective in adults with UUI. Recommendations Offer augmentation cystoplasty to patients with overactive bladder (OAB)/urgency urinary incontinence (UUI) who have failed all other treatment options and have been warned about the possible small risk of malignancy. Inform patients undergoing augmentation cystoplasty of the high risk of having to perform clean intermittent self-catheterisation (ensure they are willing and able to do so) and that they need life-long surveillance. Do not offer detrusor myectomy as a treatment for UUI. Only offer urinary diversion to patients who have failed less invasive therapies for the treatment of OAB/UUI, who will accept a stoma and have been warned about the possible small risk of malignancy.

LE 3 3 3 3 3

Strength rating Weak

Strong

Weak Weak

4.1.5 Follow-up Follow-up for women with OAB is guided by the type of treatment instituted and local service capacity. Standardisation of follow-up pathways can therefore be difficult. Here we provide recommendations based on best practice and standards from clinical trials. 4.1.5.1

Recommendations for follow-up of patients with overactive bladder

Recommendations Offer early follow up to women who have been commenced on anticholinergic or beta-3 agonist therapy. Offer repeat injections of onabotulinum toxin, as required, to women in whom it has been effective (refer to the manufacturers guidance regarding the minimum timeframe for repeat injections). Offer life-long surveillance to women who have a sacral nerve stimulation implant to monitor for lead displacement, malfunction and battery wear. Offer cystoscopic surveillance to women with an augmentation cystoplasty due to the small risk of malignancy.

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Strength rating Strong Strong

Strong Weak

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4.2

Stress Urinary Incontinence

4.2.1 Epidemiology, aetiology, pathophysiology Stress urinary incontinence, defined as ‘involuntary loss of urine on effort or physical exertion’, is a significant health problem worldwide with social and economic impact on women and society. It is estimated that the number of women in the U.S. with UI will increase from 18.3 million in 2010 to 28.4 million in 2050 [281]. The prevalence of SUI appears to peak between the ages of 45–59 years [282]. Data regarding the association of UI with ethnicity are conflicting. In several studies, SUI is more common in white women than in women of African-American or Asian-American origin [283, 284]. Other factors positively associated with SUI include parity, obesity, previous hysterectomy or pelvic surgery, diabetes mellitus [285] and pulmonary disease [286]. Physical activity level is another important factor which also positively correlates with severity of the problem [287]. Two common, often overlapping, mechanisms for SUI have been described: 1) urethral hypermobility resulting from loss of support of the bladder neck and urethra and 2) weakness of the urinary sphincter itself (intrinsic sphincter deficiency) which can result from trauma, radiotherapy, previous pelvic or urogynaecological surgery, neurological disease or ageing. The mechanism behind urethral hypermobility as a cause of SUI is based on the “vaginal hammock” hypothesis [288]. The endopelvic fascia, that is attached to the upper (abdominal) side of the PFMs, links the muscles to the vagina and represents the ‘hammock’ which can compress the urethra during both rest and activity. This compression, combined with ‘intrinsic’ urethral sphincter pressure, supports and maintains the urethra in the correct and closed position preventing involuntary loss of urine, despite any increases in intravesical pressure. Damage to the supporting tissues (particularly the arcus tendinous fasciae pelvis, the central part of the fascia) can result in hypermobility of the urethra. Consequently, rather than being compressed at times of increased intra-abdominal pressure, the urethra moves caudally funnelling the bladder neck, and is no longer compressed, resulting in SUI [288, 289]. In general, almost all treatments are used for both subtypes of SUI, but most treatments are more successful in patients with some degree of urethral hypermobility than for isolated intrinsic weakness of the urinary sphincter [290]. 4.2.2 Classification Patients with SUI can be classified as ‘uncomplicated’ and ‘complicated’ [291]. The Panel reached consensus on the definition to be used throughout this Guideline document: • Women with uncomplicated SUI: no history of prior surgery for SUI, no prior extensive pelvic surgery, no prior pelvic radiation treatment, no neurogenic LUT dysfunction, no bothersome genitourinary prolapse, absence of voiding symptoms, and no medical conditions that affect the LUT. In cases where additional significant storage symptoms, especially OAB, are present, consider a possible diagnosis of MUI (see Section 4.3). • Women with complicated SUI: previous surgery for incontinence or previous extensive pelvic surgery, a history of pelvic irradiation, the presence of anterior or apical POP, the presence of voiding symptoms or the presence of neurogenic LUT dysfunction, and with significant OAB/UUI. Neurogenic LUT dysfunction is reviewed in the EAU Guidelines on Neuro-Urology and will not be considered further in this guideline [9]. The treatment of LUTS associated with genitourinary prolapse has been included in this Guideline (see Section 4.7). 4.2.3 Diagnostic evaluation 4.2.3.1 History and physical examination There is universal agreement that taking a history should be the first step in the assessment of anyone with UI. When the history categorises UI as probable SUI the presence of complicated or uncomplicated SUI can also be determined. Those patients who require rapid referral to an appropriate specialist can also often be identified from the clinical history. There is little evidence from clinical trials that carrying out a clinical examination improves clinical outcomes, but there is widespread consensus that it remains an essential part of the assessment of women with SUI. It should include abdominal examination, vaginal examination and a careful assessment of any associated pelvic POP, examination of the perineum and evaluation of PFM strength, as well as a neuro-urological examination. An attempt to reproduce the SUI should be made. A standing cough test has a higher sensitivity for the diagnosis of SUI compared to a supine cough test [292]. Despite this, the ICS has proposed a standardisation of the female cough stress test that includes a supine/lithotomy position with 200-400 mL of fluid in the bladder and 1–4 coughs [293].

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4.2.3.1.1 Summary of evidence and recommendation for history and physical examination for SUI Summary of evidence A standing cough stress test is more sensitive than a supine test.

Recommendation Take a full clinical history and perform a thorough physical examination in all women presenting with stress urinary incontinence.

LE 1b

Strength rating Strong

4.2.3.2 Patient questionnaires Although many studies have investigated the validity and reliability of urinary symptom questionnaires and PROMs, most of these studies did not include homogenous populations of adult women diagnosed with SUI. This limits the extent to which results and conclusions from these studies can be applied in women with SUI. Some questionnaires are used for prevalence studies, others are responsive to change and may be used to measure outcomes, though evidence on their sensitivity is inconsistent [24, 25]. No evidence was found to indicate whether use of QoL or condition-specific questionnaires have an impact on the outcome of treatment. To date, there is no one questionnaire that fulfils all requirements for the assessment of women with SUI. 4.2.3.2.1 Summary of evidence and recommendation for patient questionnaires Summary of evidence Validated condition-specific symptom scores assist in the screening for, and categorisation of UI. Validated symptom scores measure the severity and bother of SUI. Both condition-specific and general health status questionnaires measure current health status, and are responsive to change following treatment.

Recommendation Use a validated and appropriate questionnaire as part of the standardised assessment of patients with stress urinary incontinence.

LE 3 3 3

Strength rating Strong

4.2.3.3 Post-void residual volume It is important to evaluate PVR in patients with SUI, in particular in patients who also have voiding symptoms or POP. The prevalence of a significant PVR in patients with SUI is uncertain, partly because of the lack of a standard definition of an abnormal PVR volume. Most studies investigating PVR have not included patients with SUI. In general, the data on PVR can only be applied with caution to adults with non-neurogenic SUI. In a cohort study of over 900 women with SUI, there was good correlation between PVR estimated by US and measured by catheterisation. The mean PVR was 39 mL measured by catheterisation and 63 mL estimated by US, with only 16% of women having a PVR > 100 mL [57]. 4.2.3.3.1 Summary of evidence and recommendations for post-void residual volume Summary of evidence The majority of women with SUI will not have a significant PVR. There is good correlation between PVR estimated using US and measured via catheterisation in women with SUI.

Recommendations Measure post-void residual (PVR) volume, particularly when assessing patients with voiding symptoms or complicated stress urinary incontinence (SUI). When measuring PVR, use ultrasound in preference to catheterisation. Monitor PVR in patients scheduled for treatment which may cause or worsen voiding dysfunction, including surgery for SUI.

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LE 3 3

Strength rating Strong Strong Strong

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4.2.3.4 Urodynamics Urodynamic testing is widely used as an adjunct to clinical diagnosis, based on the assumption that it may help to provide or confirm diagnosis. The role of urodynamics in SUI evaluation remains poorly defined and is still under debate. Invasive urodynamic tests are often performed prior to surgical treatment of SUI. Clinical diagnosis of incontinence and cystometric findings often do not correlate [67, 68]. The diagnostic accuracy of urethral pressure profilometry [69] and VLPP measurement in SUI is generally poor [294]. Measurement of MUCP correlates, although weakly, with incontinence severity [69] and there is conflicting evidence about its reproducibility [64, 65]. One method of recording MUCP cannot be compared meaningfully to another [66]. Valsalva leak point pressures are not standardised and there is minimal evidence about reproducibility. Valsalva leak point pressure did not reliably assess incontinence severity in a cohort of women selected for surgical treatment of SUI [70]. The predictive value of the tests, regarding the outcome of treatment remains unclear. A Cochrane systematic review including seven RCTs showed that the use of urodynamic tests increased the likelihood of avoiding surgery for SUI. However, there was no evidence that this influence on decision making altered the clinical outcome of treatment within trial populations [112]. A high-quality RCT (n = 630) compared office evaluation alone to office evaluation and urodynamics in women with clinical demonstrable SUI about to undergo surgery for SUI. Whilst urodynamics changed the clinical diagnosis in 56% of women [295], there was no difference in levels of SUI or any secondary outcome at twelve months follow-up after SUI surgery [80]. Another similar study also found that the omission of urodynamics was not inferior in the pre-operative work up of SUI [296]. Patients in whom urodynamics were discordant with clinical assessment (n = 109) were randomly allocated to receive either immediate surgery or individually tailored therapy based on the urodynamic findings. In this trial, performing immediate surgery, irrespective of the result of urodynamics, did not result in inferior outcomes [297]. An RCT, in which 145 women were randomised to retropubic or transobturator MUS, concluded that when patients were stratified according to pre-operative VLPP (≤ or > 60 cm H2O), it was not linked to outcome after both synthetic MUS procedures [298]. In another study conflicting evidence was reported. A VLPP or maximum urethral closure pressure in the lowest quartile was predictive in terms of failure at twelve months [83]. The Panel recognise that it may be valuable to use urodynamic test results to help select the optimum surgical procedure, but the evidence outlined above would suggest that performing urodynamics in patients with uncomplicated SUI, which can be diagnosed based on a detailed clinical history and demonstrated at examination, is not necessary. The role of urodynamics in complicated SUI is still under debate [81, 299]. However in cases of SUI with associated storage symptoms, cases in which the type of incontinence is unclear, cases where voiding dysfunction is suspected, cases with associated POP or those with a previous history of SUI surgery, the Panel consensus is that urodynamics should be carefully considered. This is in line with other guideline documents in this topic area [67]. 4.2.3.4.1 Summary of evidence and recommendations for urodynamics Summary of evidence Pre-operative urodynamics in women with uncomplicated, clinically demonstrable, SUI does not improve the outcome of surgery for SUI. There is no consistent correlation between the result of urethral function tests and subsequent success or failure of SUI surgery. There is no consistent evidence that pre-operative DO is associated with surgical failure of MUS in women.

Recommendations Do not routinely carry out urodynamics when offering treatment for uncomplicated stress urinary incontinence (SUI). Perform pre-operative urodynamics in cases of SUI with associated storage symptoms, cases in which the type of incontinence is unclear, cases where voiding dysfunction is suspected, cases with associated pelvic organ prolapse or those with a previous history of SUI surgery.

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LE 1b 3 3

Strength rating Strong Weak

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Perform urodynamics if the findings may change the choice of invasive treatment. Do not use urethral pressure profilometry or leak point pressure to grade severity of incontinence as they are primarily tests of urethral function.

Weak Strong

4.2.3.5 Pad testing Measurement of urine loss using an absorbent pad worn over a set period of time or during a protocol of physical exercise can be used to quantify the presence and severity of SUI, as well as a patient’s response to treatment. The clinical utility of pad tests for people with UI has been assessed in two systematic reviews [94, 95]. A one-hour pad test using a standardised exercise protocol and a diagnostic threshold of 1.4 g shows good specificity but low sensitivity for the diagnosis of SUI and MUI. A 24-hour pad test using a threshold of 4.4 g is more reproducible but is difficult to standardise with variation according to activity level [96]. A pad test with a specific short graded exercise protocol also has diagnostic value but a negative test should be repeated or the degree of provocation increased [97]. The usefulness of pad tests in quantifying severity and predicting outcome of treatment is uncertain [94, 99]. Pad testing is responsive to change following successful treatment [100]. Pad testing using a standardised bladder volume (50% of cystometric capacity) has been suggested to allow for a more reliable assessment of UI in a small study including 25 women [101]. There is no evidence that one type of pad test is superior to another. 4.2.3.5.1 Summary of evidence and recommendations for pad testing Summary of evidence A pad test can diagnose UI accurately, but cannot determine the aetiology. Standardisation of bladder volume and degree of provocation improves reproducibility. Twenty-four hours is sufficient duration for home-based testing balancing diagnostic accuracy and adherence. Change in leaked urine volume on standardised pad tests can be used to measure treatment outcome. Recommendations Use a pad test of standardised duration and activity protocol. Use a standardised pad test when quantification of urinary incontinence is required, especially to assess response to treatment.

LE 2 2 2 2

Strength rating Strong Weak

4.2.3.6 Imaging The role of imaging in SUI patients is limited. Many studies have evaluated imaging of bladder neck mobility by US and MRI, and concluded that SUI cannot be identified by a particular pattern of urethro-vesical movement [300]. In addition, the generalised increase in urethral mobility after childbirth does not appear to be associated with de novo SUI [301]. Studies have assessed the use of imaging to investigate the mechanism of action of MUS inserted for SUI. One study suggested that MUS placement decreased mobility of the mid-urethra but not mobility of the bladder neck [108]. Following MUS surgery, a wider gap between symphysis and sling (assessed by imaging) has been shown to correlate with a lower chance of cure of SUI [109]. One study of 72 women post-synthetic sub-urethral MUS surgery has investigated the usefulness of translabial US to assess tape functionality. In this study different parameters were measured (distance tape to urethra, position and shape during Valsalva, etc.) and concluded that tape position relative to the patient’s urethra seems to play a role in treatment outcome [302]. The general role of US in the evaluation and follow-up of women with SUI is unclear, future research is needed to establish its place in the clinical pathway. Several imaging studies have investigated the relationship between sphincter volume and function in women [303] and between sphincter volume and outcome from surgery in women [304]. However, no imaging test has been shown to predict the outcome of treatment for SUI. Imaging of the pelvic floor can identify levator ani detachment and hiatus size, although there is little evidence of a relationship to clinical benefit after treatment of SUI.

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4.2.3.6.1 Summary of evidence and recommendation for imaging Summary of evidence Imaging can reliably be used to measure bladder neck and urethral mobility, although there is no evidence of clinical benefit for patients with UI.

Recommendation Do not carry out imaging of the upper or lower urinary tract as part of the routine assessment of stress urinary incontinence.

LE 2b

Strength rating Strong

4.2.4 Disease management 4.2.4.1 Conservative management 4.2.4.1.1 Obesity and weight loss Being overweight or obese has been identified as a risk factor for LUTS and UI in many epidemiological studies [137, 138]. There is evidence that the prevalence of both UUI and SUI increases proportionately with rising BMI [305]. The proportion of patients who undergo surgery for incontinence who are overweight or obese is higher than that of the general population [139]. All the available evidence relates to women. Three systematic reviews concluded that weight loss was beneficial in improving UI [137, 138, 306]. Five further RCTs reported a similar beneficial effect on incontinence following surgical weight reduction programmes [307-311]. Two large studies in women with diabetes mellitus, for whom weight loss was the main lifestyle intervention, showed UI did not improve but there was a lower subsequent incidence of UI among those who lost weight [307, 312]. There have been other cohort studies and case-control studies suggesting similar effects, including surgery for the morbidly obese [313-317]. In a prospective study in 160 consecutive women who underwent bariatric surgery, surgically-induced weight loss was associated with a significant improvement in pelvic floor disorders, including UI [318]. Similar results reported by prospective single-centre studies investigating the effect of bariatric surgery induced weight loss, revealed that bariatric surgery was associated with substantially reduced UI at 11 months and 3 years [319, 320]. 4.2.4.1.1.1 Summary of evidence and recommendation for obesity and weight loss Summary of evidence Obesity is a risk factor for LUTS and UI in women. Non-surgical weight loss improves UI in overweight and obese women. Surgical weight loss improves UI in obese women.

Recommendation Encourage overweight and obese women with lower urinary tract symptoms/stress urinary incontinence to lose weight and maintain weight loss.

LE 3 1a 1b

Strength rating Strong

4.2.4.1.2 Urinary containment The evidence for urinary containment derives from the same literature as for containment in OAB-wet. The readers are therefore referred to Section 4.1.4.1.3. 4.2.4.1.2.1 Summary of evidence and recommendations for urinary containment Summary of evidence Pads are effective in containing urine.

Recommendations Ensure that women with stress urinary incontinence (SUI) and/or their carers are informed regarding available treatment options before deciding on urinary containment alone. Offer incontinence pads and/or containment devices for management of SUI, either for temporary symptom control or where other treatments are not feasible.

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LE 1b

Strength rating Strong Strong

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4.2.4.1.3 Pelvic floor muscle training Pelvic floor muscle training is used to improve function of the pelvic floor, thus improving urethral stability. An immediate effect of a single PFM contraction is narrowing of the levator hiatus area, increase of urethral closure pressure and lift of the bladder and rectum preventing the occurrence of UI [321-323]. In an RCT comparing intensive PFMT over a six-month period with no treatment, authors reported increased muscle strength and endurance, narrowing of the levator hiatus, reduced PFM length, increased muscle volume and lift of the bladder neck and rectal ampulla [324]. Pelvic floor muscle training may be used to prevent UI, e.g. in childbearing women before birth, or as part of a planned recovery programme after childbirth. Most often, PFMT is used to treat existing SUI; sometimes in combination with observation and/or palpation of the muscle contraction by the therapist or biofeedback (by use of an apparatus measuring the contraction either by electromyography (EMG), manometry, dynamometry, US or MRI). Electrical stimulation and vaginal cones are also used in treatment of SUI based on an assumption of the same mechanism of action. 4.2.4.1.3.1 Efficacy of pelvic floor muscle training in stress urinary incontinence A Cochrane systematic review compared PFMT with no treatment or inactive control treatment and found that women with SUI in the PFMT groups were eight times more likely to report cure (56% vs. 6%; 4 trials including 165 women; high-quality evidence) [325]. The review also documented significant improvement in UI (7 trials, 376 women; moderate-quality evidence), and improvement in UI QoL (6 trials, 348 women; low-quality evidence). Pelvic floor muscle training reduced leakage by one episode per day in women with SUI (7 trials, 432 women; moderate-quality evidence). Women with SUI in the PFMT groups lost significantly less urine in short (up to one hour) pad tests. The comparison of short pad tests showed considerable heterogeneity but the findings still favoured PFMT when using a random-effects model (mean difference 9.71 g in 4 trials including 185 women; moderate-quality evidence). Women in the PFMT group were also more satisfied with treatment and their sexual outcomes were better. Adverse events were rare and minor. A Cochrane review concluded that there may be some additional effect of adding biofeedback to PFMT. However, this was based on RCTs with training dosage and attention favouring biofeedback [326]. In a recent RCT (61.3% had MUI) comparing the exact same training dosage and attention between groups, use of biofeedback did not yield any additional effect [327]. Group training is cost effective in treatment of SUI/ UI compared to individual treatment [328]. A Cochrane review concluded that a combination of individual assessment/education and group training was equally effective compared to individual treatment, but again the dosage and attention differed between comparison groups [329]. In a more recent RCT with the exact same training dosage and attention in individual and group training, group training was not inferior to individual treatment [328]. It is worth noting that all of the PFMT interventions in these reviews follow individual assessment and teaching before starting PFMT, and most interventions use some sort of measurement tool (biofeedback) in the assessment. Both the Cochrane review and the ICI concluded that the use of vaginal cones to train the PFM is more effective than no treatment, but it is inconclusive whether it is more or less effective than structured PFMT [325, 330, 331]. Some women are unable to maintain the cone inside, some report discomfort and motivation problems and adherence may be low [330]. The Cochrane review [325], the ICI [331] and the National Institute for Health and Care Excellence (NICE) guidelines (2019) [67] all conclude that there is the highest level evidence (1a) to support PFMT in the treatment of SUI/MUI. All systematic reviews conclude that PFMT is less effective if women with MUI and UUI are included in the studies and more effective with more intensive and supervised training. According to the NICE guidelines literature review, PFMT is as effective as surgery for around half of women with SUI, and due to the risks following surgery and absence of side effects of PFMT, they recommend three months of supervised PFMT as first-line treatment for SUI and MUI [67]. Pelvic floor muscle training was compared to synthetic MUS surgery in an RCT involving 460 women with moderate to severe SUI [332]. Crossover between treatment arms was allowed and 49.0% of women in the physiotherapy group and 11.2% of women in the surgery group crossed over to the alternative treatment. Subjective improvement was reported by 90.8% of women in the surgery group and 64.4% of women in the physiotherapy group at 12 months. 4.2.4.1.3.2 Efficacy of electrical stimulation There is lack of consensus regarding the use of ES to treat SUI. For subjective cure of SUI, a Cochrane review found moderate quality evidence that ES is probably better than no active treatment (risk ratio [RR] 2.31) [333]. Similar results were found for cure or improvement of SUI (RR: 1.73), but the quality of evidence was low. There

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is uncertainty as to whether there is a difference between ES and sham treatment in terms of subjective cure alone because of very low quality of evidence (RR: 2.21). For subjective cure or improvement, ES may be better than sham treatment (RR: 2.03). Any comparison between ES and PFMT and other treatments is hampered by low quality evidence. Side effects such as pain and discomfort have been reported, and ES is not tolerated by all women [333]. In an RCT, 132 women assessed by vaginal palpation to have 0-1 on the modified Oxford grading scale (unable to contract the PFM) were randomly assigned to an 8-week intervention of either learning to contract via palpation, palpation with pelvic tilt, intravaginal ES or verbal instruction [334]. The results showed that 63.6%, 69.7%, 33.3% and 18.2% in the four groups, respectively, scored 2 after the intervention. Palpation was significantly more effective that ES, but one third of the ES group had learned a correct PFM contraction [334]. The effect on UI measured by ICIQ-UI-SF was significantly better in the palpation group. 4.2.4.1.3.3 Long-term efficacy of pelvic floor muscle training In a systematic review including 19 studies, 1,141 women were followed-up long term (between 1 and 15 years) after PFMT for SUI [335]. Meta-analysis was not performed due to high heterogeneity of outcome measures and training dosage (frequency, intensity, duration and adherence). Only two studies provided interventions during the follow-up period. Losses to follow-up during the long-term period ranged between 0% and 39%. Long-term adherence to PFMT varied between 10% and 70%. Five studies reported that the initial success rate on SUI and MUI was maintained at long term. Long-term success based on responders in the original trial varied between 41% and 85%. Surgery rates at long term varied between 4.9% and 58%. It was concluded that short-term outcome of PFMT can be maintained at long-term follow-up without incentives for continued training, but there is a high heterogeneity in both interventional and methodological quality in short- and longterm PFMT studies [335]. 4.2.4.1.3.4 Efficacy of pelvic floor muscle training in childbearing women Pelvic floor muscle training to prevent SUI has been studied during pregnancy and in the postpartum period and the results are not reported separately for SUI and other subgroups of UI. A Cochrane review concluded that PFMT in women with and without UI (combined primary and secondary prevention) during pregnancy, produced a 26% reduced risk of UI during pregnancy and the mid-postnatal period [336]. Furthermore, pregnant continent women (primary prevention) who exercise the PFM during pregnancy are 62% less likely to experience UI in late pregnancy and have 29% lower risk of UI 3 to 6 months after giving birth. To date there is insufficient evidence for a long-term effect of antenatal PFMT beyond 6 to 12 months postpartum. In treatment studies; compared with “usual” care, there is no evidence that antenatal PFMT in incontinent women decreases incontinence in late pregnancy (very low-quality evidence), or in the mid- (low-quality evidence), or late postnatal periods (very low-quality evidence). There are fewer RCTs in the postpartum period than during pregnancy [336]. No primary prevention studies were found in women after birth. For PFMT started after delivery, in a mixed group of continent and incontinent women, there was uncertainty about the effect on UI risk in the late postnatal period (3 trials, 826 women; moderate-quality evidence), and in postnatal women with persistent UI, there is no evidence that PFMT results in a difference in UI at more than six to twelve months postpartum (3 trials; 696 women; low-quality evidence). However, another RCT found that UI was less frequent in the intervention group, with 57% of patients still symptomatic, compared to 82% of controls (p = 0.03), as was bladder-related bother with a prevalence of 27% in the intervention vs. 60% in the control group (p = 0.005) [337]. Randomised controlled trials of high interventional and methodological quality are needed in the postpartum period. 4.2.4.1.3.5 Pelvic floor muscle training in the elderly There are few RCTs on conservative treatment of SUI in the elderly (> 65 years) and many of the studies combine different modalities e.g. bladder training, lifestyle modifications and PFMT [338]. Some of the studies on PFMT and SUI in the general population have included women > 65 years and PFMT seems to be equally effective in elderly women. A systematic review on conservative management included 23 trials, 9 of moderate to high methodological quality, and concluded that PFMT in combination with physical training was effective in reducing UI and improving QoL [339]. Prompted voiding and toileting assistance with functional exercise reduced UI. Other behavioural interventions such a night-time prompted voiding and waking routine had no effect on UI reduction. The most recent ICI consensus publication stated that although there are limited studies of PFMT on UI in frail elderly populations, age and frailty alone should not preclude the use of PFMT in appropriate patients with sufficient cognition to participate [338]. More high-quality RCTs, both in frail and healthy older women (> 80 years of age) are needed.

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4.2.4.1.3.6 Summary of evidence and recommendations for pelvic floor muscle training Summary of evidence Pelvic floor muscle training is better than no treatment for improving SUI and QoL in women with SUI and MUI across a range of outcomes including cure rate, improvement rate, QoL, number and volume of urine leaks and treatment satisfaction. Pelvic floor muscle training exhibits a low rate of adverse events. Higher-intensity, supervised, treatment regimens confer greater benefit in women receiving PFMT. There is no extra benefit of combining PFMT with biofeedback. Short-term benefits of intensive PFMT can be maintained in the long-term. Pelvic floor muscle training in the antenatal period is associated with a reduced risk of UI in late pregnancy and in the short-term post-natally. Postpartum PFMT is effective in women with persistent UI. There is no benefit of postpartum PFMT in mixed (continent and incontinent) groups of women. Mid-urethral sling surgery is superior to PFMT for women with moderate to severe SUI. Pelvic floor muscle training commencing in the early postpartum period improves UI in women for up to 6 months. There is conflicting evidence on whether the addition of ES increases the effectiveness of PFMT alone. Recommendations Offer supervised intensive pelvic floor muscle training (PFMT), lasting at least three months, as first-line therapy to all women with stress urinary incontinence (SUI) or mixed urinary incontinence (MUI) (including the elderly and pre- and post-natal). Ensure that PFMT programmes are as intensive as possible. Balance the efficacy and lack of adverse events from PFMT against the expected effect and complications from invasive surgery for SUI. Do not offer electrical stimulation with surface electrodes (skin, vaginal, anal) alone for the treatment of SUI.

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1a 1a 1b 2a 1a 1b 1b 1b 1b 2a

Strength rating Strong

Strong Strong Strong

4.2.4.1.4 Electromagnetic stimulation Electromagnetic stimulation (EMS) has been evaluated for its role in SUI therapy. In a double-blind RCT of EMS including 70 women with SUI, no effect of EMS over sham in any outcome was recorded [340]. 4.2.4.2 Pharmacological management 4.2.4.2.1 Oestrogen Oestrogenic drugs including conjugated equine oestrogens, oestradiol, tibolone and raloxifene, are used as hormone replacement therapy (HRT) for women with natural or therapeutic menopause. Oestrogen treatment for SUI has been tested using oral, transdermal and vaginal routes of administration. Available evidence suggests that vaginal oestrogen treatment with oestradiol and oestriol is not associated with the increased risk of thromboembolism, endometrial hypertrophy, and breast cancer seen with systemic administration [243-245]. Vaginal (local) treatment is primarily used to treat symptoms of vaginal atrophy in post-menopausal women. A Cochrane systematic review looked at the use of oestrogen therapy in post-menopausal women given local oestrogen therapy and 17 studies are focused on SUI [243]. There is also a narrative review of oestrogen therapy in urogenital diseases [341]. The Cochrane review found that vaginal oestrogen treatment improved symptoms of SUI in the short term [243]. The review found small, low-quality trials comparing vaginal oestrogen treatment with phenylpropanolamine, PFMT, ES and its use as an adjunct to surgery for SUI. Local oestrogen was less likely to improve UI than PFMT but no differences in UI outcomes were observed for the other comparisons. A single trial of local oestrogen therapy comparing a ring device to pessaries found no difference in UI outcomes although more women preferred the ring device. In one trial no significant adverse effects following vaginal administration of oestradiol for vulvovaginal atrophy over two years were reported [342]. Vaginal oestrogen therapy can be given as conjugated equine oestrogen, oestriol or oestradiol in vaginal pessaries, vaginal rings or creams. The ideal treatment duration and the long-term effects are uncertain. A review of local oestrogen treatment showed improvement of UI over placebo with vaginal rings, which were favoured subjectively over pessaries [343].

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One RCT in post-menopausal women showed benefit in adding intravaginal oestriol to vaginal ES and PFMT in female SUI [344]. Studies of systemic HRT with non-urogenital primary outcomes have looked for change in urinary continence in secondary analyses. Large trials using conjugated equine oestrogens showed a higher rate of development or worsening of UI compared to placebo and no SUI improvement [345-350]. In a single RCT, use of raloxifene was not associated with development or worsening of UI [351]. Three small RCTs using oral oestriol or oestradiol as HRT for vulvovaginal atrophy suggested that UI symptoms were improved although the evidence was unclear [67, 352, 353]. 4.2.4.2.1.1 Summary of evidence and recommendations for oestrogens Summary of evidence Vaginal oestrogen therapy improves SUI for post-menopausal women in the short term. Neoadjuvant or adjuvant use of local oestrogens are ineffective as an adjunct to surgery for SUI. Systemic hormone replacement therapy using conjugated equine oestrogens does not improve SUI and may worsen pre-existing UI.

Recommendations Offer vaginal oestrogen therapy to post-menopausal women with stress urinary incontinence (SUI) and symptoms of vulvo-vaginal atrophy. In women taking oral conjugated equine oestrogen as hormone replacement therapy who develop or experience worsening SUI discuss alternative hormone replacement therapies.

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Strength rating Strong Strong

4.2.4.2.2 Duloxetine Duloxetine inhibits the presynaptic re-uptake of neurotransmitters, serotonin (5-HT) and norepinephrine (NE). In the sacral spinal cord, an increased concentration of 5-HT and NE in the synaptic cleft increases stimulation of 5-HT and NE receptors on the pudendal motor neurons, which in turn increases the resting tone and contraction strength of the urethral striated sphincter. Duloxetine was evaluated as a treatment for female SUI or MUI in three systematic reviews [162, 354, 355]. Improvement in UI compared to placebo was observed with no clear differences between SUI and MUI. One study reported cure for UI in about 10% of patients. An improvement in the Urinary Incontinence Quality of Life questionnaire (I-QoL) was not found in the study, which used this as a primary endpoint. In a further study comparing duloxetine, 80 mg daily, with PFMT alone, PFMT + duloxetine, and placebo [356], duloxetine reduced leakage compared to PFMT or no treatment. Global improvement and QoL were better for combined therapy than no treatment. There was no significant difference between PFMT and no treatment in this trial. Two open-label studies with a follow-up of one year or more evaluated the long-term effect of duloxetine in controlling SUI [357, 358]. Both studies had a high patient withdrawal rate, due to lack of efficacy and a high incidence of adverse events, including nausea and vomiting (40% or more of patients), dry mouth, constipation, dizziness, insomnia, somnolence and fatigue, amongst other causes. A systematic review showed significant efficacy for duloxetine compared to placebo in women with SUI, but with increased risk of adverse events [355]. The reported adverse effects of duloxetine include mental health problems and suicidal ideation. A meta-analysis of four RCTs including 1,910 women with SUI reported that “no suicidality, violence or akathisia events were noted”, but suggested that the discontinuation rate due to adverse events was around 1 in 7 and that the harms of this treatment may outweigh the benefit [359]. Furthermore, a meta-analysis of twelve placebo-controlled trials involving almost 3,000 patients showed that in patients with major depressive disorders there were no significant differences in the incidence of suiciderelated events with duloxetine vs. placebo [360]. 4.2.4.2.2.1 Summary of evidence and recommendations for duloxetine Summary of evidence Duloxetine improves SUI in women, but the chances of cure are low.

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Duloxetine may cause significant gastrointestinal and central nervous system side effects leading to a high rate of treatment discontinuation, although these symptoms may be limited to the first weeks of treatment.

1a

Recommendations Strength rating Strong Offer duloxetine (where licensed) to selected patients with SUI unresponsive to other conservative treatments and who want to avoid invasive treatment, counselling carefully about the risk of adverse events. Duloxetine should be initiated and withdrawn using dose titration because of the high risk of Strong adverse events. 4.2.4.3 Surgical management 4.2.4.3.1 General considerations The use of polypropylene mesh, synthetic MUS for the treatment of SUI, has recently come under scrutiny following concerns raised regarding long-term complications. In some European countries such as the United Kingdom the use of synthetic MUS has been paused and pelvic mesh was the subject of a UK parliamentary review published in July 2020 [361]. This review has concluded that “For many women mesh surgery is troublefree and leads to improvements in their condition. However, this is not the case for all. There is no reliable information on the true number of women who have suffered complications. While they may be in the minority, that does not diminish the catastrophic nature of their suffering or the importance of providing support to them and learning from what has happened to them”. The range of complications highlighted during the process of this parliamentary review included [361]: • pain; • recurrent infections; • mobility issues; • recurring or new incontinence/urinary frequency; • recurring or new prolapse; • haemorrhage; • bowel issues; • erosion of mesh; this can be into the vagina and/or other organs; • sexual difficulties; including pain on intercourse and a loss of sex life; • autoimmune issues; • psychological impacts. When considering the choice of surgical treatments for SUI the Panel would advise individual clinicians to abide by any national or local rules that may be in place regarding mesh surgery. Furthermore it is essential for clinicians to point out the deficiencies in the long-term evidence regarding mesh use in SUI with specific reference to the complications highlighted above. In line with the recommendations from NICE [67] and the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) paper [362] the Panel agreed that surgeons and centres performing surgery should: • be trained in the field of incontinence and for each surgical procedure they perform/offer; • perform sufficient numbers of a procedure to maintain expertise of him/herself and the surgical team; • be able to offer alternative surgical treatments; • be able to deal with the complications of surgery; • provide suitable arrangements for long-term follow-up. Furthermore, the establishment of accurate and complete databases registering the interventions, patient profile and surgical complications or all surgical treatments for SUI is recommended to allow the generation of robust long-term data. Many surgical procedures are available for uncomplicated SUI patients and the Panel analysed the results of the different procedures in terms of clinical effectiveness, safety and cost-effectiveness based on the recent ESTER systematic review and economic evaluation [363] and previous systematic reviews including those from the Cochrane collaboration [364-368].

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The outcome parameters used to evaluate surgery for SUI have been limited to: • continence rate; • patient-reported outcome measures; • general and procedure-specific complications; • generic, specific (UI) and associated (sexual and bowel) QoL. In this context, it has to be taken into account that a number of products may no longer be available and therefore the recommendations may not be transferable to current devices. The Panel makes a strong recommendation that new devices are only used as part of a structured research programme and their outcomes monitored in a registry, until there is adequate evidence of safety and efficacy. 4.2.4.3.1.1 Recommendations for surgical treatment of SUI Recommendations Strength rating Offer patients who have explored/failed conservative treatment options a choice of different Strong surgical procedures, where appropriate, and discuss the advantages and disadvantages of each approach. Use new devices for the treatment of SUI only as part of a structured research programme. Strong Their outcomes must be monitored in a registry or as part of a well-regulated research trial. 4.2.4.3.2 Surgery for women with uncomplicated stress urinary incontinence The principal procedures evaluated are: • open and laparoscopic colposuspension; • autologous “traditional” slings; • bulking agents; • synthetic MUS. 4.2.4.3.2.1 Open- and laparoscopic colposuspension surgery Open colposuspension was previously considered the most appropriate surgical intervention for SUI, and was used as the comparator in RCTs of newer, less invasive, surgical techniques. These include laparoscopic techniques, which have enabled colposuspension to be performed with a minimally invasive approach. Open colposuspension A number of systematic reviews were found, which covered the subject of open surgery for SUI, with a large number of RCTs [363, 365-368]. The Cochrane review on open colposuspension [368] included 55 trials comprising 5,417 women. In most of these trials, open colposuspension was used as the comparator to an experimental procedure. Within the first year, complete continence rates of approximately 85–90% were achieved for open colposuspension, while failure rates in terms of recurrent UI were 17% up to five years and 21% at over five years. The risk of re-operation after Burch colposuspension is estimated at 6% within 5 years [112] and 10.8% within 9 years [113]. The re-operation rate specifically for UI was only 2%. Colposuspension was associated with a higher rate of development of enterocoele/vault/cervical prolapse (42%) and rectocele (49%) at five years compared to TVT (23% and 32%, respectively). The rate of cystocoele was similar postcolposuspension (37%) and after TVT (41%). The Cochrane review concluded that open colposuspension is an effective treatment for SUI and around 70% of women can expect to be dry at five years after surgery. Laparoscopic colposuspension A Cochrane review reported on twelve trials comparing laparoscopic colposuspension to open colposuspension [366]. Although these procedures had a similar subjective cure rate, there was limited evidence suggesting the objective outcomes were less good for laparoscopic colposuspension. The ESTER systematic review [363] showed, based on a network meta-analysis, that at 12 months open colposuspension was more effective than laparoscopic colposuspension (9 trials, OR: 0.68, p = 0.009) but these findings are based on low quality evidence. The Surface Under the Cumulative Ranking Scores (SUCRA), which is a numerical representation of the overall ranking and presents a single number associated with each intervention, were 76.7% after open colposuspension, and 48.9% after laparoscopic colposuspension (out of a maximum score of 100%). Laparoscopic colposuspension had a shorter duration of surgery and subsequent hospital stay and may be slightly more cost-effective when compared with open colposuspension after 24 months follow-up. Single-port laparoscopic Burch can be an alternative treatment, although data confirming efficacy are limited [369].

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Complications Voiding difficulties appeared to be more common after laparoscopic colposuspension than after retropubic MUS (7.5% vs. 5.1%) [363]. There was no evidence of a difference for the comparison assessing open colposuspension vs. retropubic MUS (7.8% vs. 7.5%; OR: 0.87) [363]. The results for the comparisons of de novo symptoms of urgency or UUI between open colposuspension and retropubic MUS (11% vs. 8%, OR: 1.49) did not favour either treatment and showed wide confidence intervals [363]. The rate of bladder or urethral perforation was higher for laparoscopic colposuspension compared with open colposuspension (3.7% vs. 0.7%; OR: 4.65) [363]. 4.2.4.3.2.1.1 Summary of evidence and recommendation for open- and laparoscopic colposuspension surgery for stress urinary incontinence Summary of evidence High subjective cure rates are associated with both open- and laparoscopic colposuspension for the treatment of SUI. Objective cure rates are higher for open colposuspension compared to laparoscopic colposuspension. Colposuspension is associated with a higher long-term risk of POP than MUS. Laparoscopic colposuspension has a shorter hospital stay and may be more cost-effective than open colposuspension. Laparoscopic colposuspension is associated with higher rates of intra-operative bladder perforation and post-operative voiding dysfunction compared to open colposuspension. The rates of de novo urinary urgency following colposuspension are similar to other surgical treatments for SUI.

LE 1a 1a 1a 1a 1a 1a

Recommendation Strength rating Strong Offer colposuspension (open or laparoscopic) to women seeking surgical treatment for stress urinary incontinence following a thorough discussion of the risks and benefits relative to other surgical modalities.

4.2.4.3.2.2 Autologous sling In the past, autologous, cadaveric, xenograft, and synthetic materials have been used for bladder neck  pubovaginal sling (PVS). Nowadays, use of autologous tissue, either rectus sheath or fascia lata, is the most studied material with the strongest evidence base to support its use [370]. The ESTER systematic review included 3 trials of autologous sling vs. open colposuspension, six trials of autologous sling vs. retropubic MUS and one trial comparing autologous sling vs. transobturator MUS. The quality of evidence was overall very low. The pooled estimate showed that fascial sling had a higher cure rate at one year, than open colposuspension (OR: 1.24), retropubic MUS (OR: 1.06) and transobturator MUS (OR: 1.44) but without statistical significance. The SUCRA score was 89.4% for women cured after autologous fascial sling. A sub-analysis from a Cochrane review showed autologous slings had better effectiveness compared to colposuspension at one to five years follow-up [368]. In an RCT of Burch colposuspension vs. autologous slings complete continence rates decreased substantially over time in both arms. At five years, the continence rate of colposuspension was 24.1% compared to 30.8% for fascial slings. Satisfaction remained higher in the sling group (83% vs. 73%) and was directly related to the continence status [371]. Complications Adverse events rates were similar for the two treatment groups (Burch 10% and sling 9%) although postoperative obstruction was found exclusively in the sling group. Voiding difficulties appear to be more common after autologous sling [15.4% vs. 10.2%; OR: 1.46] than after retropubic MUS. Compared with open colposuspension, the rate of bladder or urethral perforation was lower for traditional sling [0.6% vs. 3.0%; OR: 0.20] [363]. 4.2.4.3.2.2.1 Summary of evidence and recommendation for autologous sling Summary of evidence High cure rates are associated with autologous sling placement for the treatment of SUI. Autologous sling is more effective in terms of cure rate than colposuspension.

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Autologous sling has a similar rate of adverse events compared to open colposuspension, with higher rates of voiding dysfunction and post-operative UTI, but a lower rate of bladder- or urethral perforation. Recommendation Offer autologous sling placement to women seeking surgical treatment for stress urinary incontinence following a thorough discussion of the risks and benefits relative to other surgical modalities.

1a

Strength rating Strong

4.2.4.3.2.3 Urethral bulking agents The concept of this procedure originates from the idea that intra- or peri-urethral injection of an agent able to form artificial cushions under/around the urethra will increase the resistance at the bladder outlet and facilitate continence. Two Cochrane reviews (2012 and updated in 2017) identified fourteen RCTs or quasi-RCTs of treatment for UI in which at least one management arm involved peri-urethral or transurethral injection therapy [372, 373]. Following this review, five additional reviews investigated the effect of injectables for the treatment of female SUI [374-378], independently of the injected material. One review included results from RCTs only [378]. In the most recent Cochrane systematic review, 1,814 patients were included from fourteen trials of seven different types of intra-urethral injection: glutaraldehyde cross-linked collagen (Contigent©), a porcine dermal implant (Permacol©), solid silicone elastomer (Macroplastique©), autologous fat, pyrolytic carbon (Durasphere©), calcium hydroxylapatite (Coaptite©), hydrogel (Bulkamid®) and dextran polymer (Zuidex©). The conclusions state that “the available evidence base remains insufficient to guide practice” [373]. A systematic review of 23 studies using Macroplastique© including 958 patients showed a 75% improvement with 43% dry rate at less than 6 months and a 64% improvement and 36% cure rate at more than 18 months [375]. A review of 514 elderly women with SUI treated with various agents showed a reduced pad weight in 73% at 1-year follow-up, independent of the material injected [379]. The heterogeneity of the populations, the variety of materials used and the lack of long-term follow-up limit guidance of practice. Most of the studies show a tendency for a short-term improvement in UI, with the exception of one RCT, which could not find a difference between saline and fat injection [380]. One trial of 30 women showed a weak (but not clinically significant) advantage in terms of patient satisfaction after mid-urethral injection in comparison to bladder neck injection but with no demonstrable difference in continence levels [373]. Two trials found a higher risk of urinary retention with intra-urethral injections compared with transurethral injections, although the latter is associated with a higher risk of temporary urinary retention [372, 381]. A small RCT found no difference in efficacy between mid-urethral and bladder neck injection of collagen [382]. One study treated patients who had received radiotherapy with injection of Bulkamid® and reported around 25% cure at short-term follow-up [383]. Bulking agent injection is generally safe, the most frequent adverse event being UTI. However, autologous fat or hyaluronic acid should not be used due to the risk of fatal embolism and local abscess formation, respectively [372, 380]. Comparison with other surgical procedures Two RCTs compared collagen injection to conventional surgery for SUI (silicon particles vs. autologous sling and collagen vs. other surgical procedures). The studies reported greater efficacy but higher complication rates for open surgery [384, 385]. In a recent non-inferiority clinical trial women with primary SUI were randomised to TVT or polyacrylamide hydrogel urethral bulking agent injection (Bulkamid®) [386]. Mid-urethral TVT slings were associated with better satisfaction and cure rates than Bulkamid® in primary SUI. In term of objective cure rate the cough stress test was negative in 95.0% of patients who underwent TVT vs. 66.4% who underwent Bulkamid®. 4.2.4.3.2.3.1 Summary of evidence and recommendations for urethral bulking agents Summary of evidence Urethral bulking agents may provide short-term improvement and cure, in women with SUI.

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Bulking agents are less effective than MUS, colposuspension or autologous sling for cure of SUI and repeat injections may be required in order to achieve sustained benefits. Autologous fat and hyaluronic acid as bulking agents have a higher risk of adverse events. Adverse event rates for urethral bulking agents are lower compared to open surgery. There is no evidence that one type of bulking agent is better than another type. The peri-urethral route of injection of bulking agents may be associated with a higher risk of urinary retention compared to the transurethral route. Recommendations Offer urethral bulking agents to women seeking surgical treatment for stress urinary incontinence (SUI) following a thorough discussion of the risks and benefits relative to other surgical modalities. Offer urethral bulking agents to women with SUI who request a low-risk procedure with the understanding that efficacy is lower than other surgical procedures, repeat injections are likely and long-term durability and safety are not established. Do not offer autologous fat and hyaluronic acid as urethral bulking agents due to the higher risk of adverse events.

1b 1a 2a 1b 2b

Strength rating Strong

Strong

Strong

4.2.4.3.2.4 Mid-urethral slings Early clinical studies identified that non-autologous synthetic slings should be made from monofilament, nonabsorbable material, typically polypropylene, constructed as a 1–2 cm wide mesh with a relatively large pore size (macroporous) and coloured to facilitate removal [387]. Mid-urethral slings are now the most frequently used surgical intervention in Europe for women with SUI. Transobturator route versus retropubic route A Cochrane meta-analysis of MUS procedures for SUI in women was performed in 2017 spanning January 1947 to June 2014 [388]. Moderate quality evidence from 55 studies showed variable, but comparable, subjective cure rates between retropubic and transobturator slings (62–98% in the transobturator groups and 71–97% in the retropubic groups) in the short term (up to one year). No difference in the objective cure rate in the short term was found. However, the ESTER systematic review [363], based on a network meta-analysis including 36 trials of overall moderate quality, showed that at 12 months retropubic MUS was, on average, more effective than transobturator MUS (OR: 0.74); SUCRA scores for women cured after retropubic MUS were 89.1% vs. 64.1% after transobturator MUS. However there was no statistically significant difference in these cure rates between the two approaches (p = 0.4). Similarly, based on 40 moderate quality trials, retropubic MUS performed better than the transobturator approach in terms of symptom improvement (RR: 0.76) but the difference was again not statistically significant (p = 0.16). Analysis of a randomised equivalence trial of retropubic vs. transobturator MUS for the treatment of SUI in women shows similar findings. This trial confirms equivalence of objective cure rates at 12 months but not at 24 months (77.3% and 72.3% objective cure rate for retropubic and transobturator surgery). For both types of MUS subjective and objective treatment success decreased over time and equivalence of the retropubic and the transobturator routes could not be confirmed at 24 and 60 months with retropubic demonstrating a slightly increased level of benefit, despite satisfaction remaining high in both arms [389]. Five years after surgical treatment objective success was 7.9% greater in women assigned to retropubic sling compared to transobturator sling (51.3% vs. 43.4%), not meeting pre-specified criteria for equivalence. Patient satisfaction decreased over 5 years but remained high and similar between treatment arms (retropubic sling 79% vs. transobturator sling 85%, p = 0.15) [390]. In terms of long-term complications, data are scant but in one study de novo OAB developed in 14% of patients at ten years with no significant differences between groups (TOT vs. TVT) [391]. In a multicentre prospective study of women undergoing TOT a history of failure of previous anti-incontinence procedures was the only predictor of recurrence of SUI (HR: 5.34, p = 0.009) [391]. A long-term cohort study of retropubic TVT showed an 89.9% objective cure rate and a 76.1% subjective cure rate at ten years. Overall, 82.6% of patients reported to be highly satisfied with the surgery [392]. A long-term prospective study on transobturator sling showed that at 145 months the objective and subjective cure rates were 78.9% and 62.6% respectively; with no significant deterioration in SUI cure rates over time [393]. Another longterm follow-up study of patients treated with TVT showed a sustained response with 95.3%, 97.6%, 97.0% and 87.2% of patients being cured or improved at 5, 7, 11 and 17 years, respectively [394].

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The ESTER network meta-analysis based on cure and improvement suggested that, when comparing surgical treatments for SUI, retropubic MUS, transobturator MUS and traditional sling had the highest efficacy rates, but this ranking does not consider the complication profile of these techniques. The short- to medium-term adverse event data were sparse [363]. The nine procedures compared in ESTER with their associated SUCRA ratings are shown in Table 3 below. Table 3: SUCRA curve values for the outcome - number of women cured (indicated by %)* Procedure* Traditional sling operations Retropubic MUS operations Open colposuspension Transobturator MUS operations Laparoscopic colposuspension Single-incision sling operations Bladder neck needle suspension Anterior vaginal repair. PFMT

Number of women cured 89.4% 89.1% 76.7% 64.1% 48.9% 39.8% 26.9% 12.5% 2.6%

*Adapted from ESTER [363]. Several health economic analyses of MUS procedures have been published with conflicting results. In a review of 26 economic evaluations and on the basis of a cost-utility and value of information analysis over a 10-year time period, the authors concluded that MUS remains among the most cost-effective approaches [364]. A primary economic evaluation of retropubic vs. transobturator tapes over a 5-year time period suggested that the latter may be cost-effective and cost-saving compared to the standard TVT approach [395]. Conversely, the findings from the ESTER network meta-analysis stated that over a lifetime, retropubic MUS was, on average, the least costly and most effective surgery but the level of uncertainty in these analyses was high. Insertion using a skin-to-vagina direction versus a vagina-to-skin direction The Cochrane review on MUS for female SUI showed no difference in the short- and medium-term subjective cure rates in vagina-to-skin (inside-out) vs. skin-to-vagina (outside-in) approaches based on moderate quality evidence [396]. Voiding dysfunction seems to be more frequent in the vagina to skin (inside-out) TOT group but this approach is associated with a lower frequency of vaginal perforations (RR: 0.25). Due to the low quality of the evidence it is unclear whether the lower frequency of vaginal perforations of this approach is responsible for the observed lower rate of vaginal tape erosions. Likewise, a further meta-analysis of RCTs demonstrated no significant difference in efficacy between outsidein vs. inside-out approaches, but vaginal perforations were, again, less frequent in the latter group (2.6% vs. 11.8%, OR: 0.21, p = 0.0002) [397]. The five-year data of a prospective, non-randomised study of the two techniques showed a very high objective success rate (82.6 vs. 82.5%, respectively) with no difference between the two approaches [398]. In a secondary analysis of the E-TOT study (a study of transobturator TVTs in the treatment of women with urodynamic MUI), no difference in the patient-reported success rates was found between the vagina-to-skin (inside-out) and the skin-to-vagina (outside-in) groups (63.2% and 65.5%, respectively; OR: 1.11) at 9 years follow-up [399]. Complications of synthetic mid-urethral slings In the ESTER network meta-analysis it was noted that comparative assessment of adverse events between different procedures was not always possible due to the lack of available data [363]. Direct comparisons using head-to-head meta-analyses were mainly carried out for retropubic MUS, transobturator MUS or single-incision slings. The authors did, however, comment that “For other intervention comparisons, the number of studies was generally small and the CIs wide. However, there was some evidence to suggest that bladder perforation was more likely to occur after retropubic MUS than after transobturator MUS, open colposuspension or traditional sling”. In particular, the retropubic approach for MUS was associated with a significantly higher rate of bladder perforation than transobturator MUS (5% vs. 0.2%). Regarding de novo voiding dysfunction, 36 studies compared transobturator MUS with retropubic MUS, favouring transobturator MUS (OR: 0.51). While for pain, it is worth pointing out that it was defined and measured in many different ways across individual trials and across Cochrane systematic reviews. Some pain outcomes were categorised

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by location (e.g. suprapubic) or time (e.g. short- or long-term). These discrepancies made it difficult to combine data from different studies. Data were available mainly for the comparison between retropubic MUS and transobturator MUS and other surgical procedures. However, groin pain was more frequent after transobturator MUS than retropubic MUS [6.3% vs. 1.3%; OR: 3.80]. Converse findings were reported for suprapubic pain which was higher following TVT (1.2% vs. 4.0%; OR: 0.37). Visceral injury (0.5% vs. 2.4% OR: 0.36), mean operative time, operative blood loss and hospital stay were lower in the transobturator groups than retropubic MUS. The overall vaginal erosion risk was low and comparable in both groups [363]. The rate of tape/mesh exposure or extrusion between retropubic and transobturator MUS was similar (2.1% vs. 2.4%; OR: 1.10). The exact time points at which measurements occurred could not be derived from the Cochrane systematic reviews but most studies were reported to have a short follow-up period (≤ 12 months), with only a few studies having a follow-up period of ≥ 2 years [363]. Re-do surgery for UI was more common in the transobturator group (RR = 8.79); however the data are limited and of low quality. A population-based study performed in Scotland in over 16,000 women operated on for SUI showed a similar rate of complications between mesh and non-mesh surgery [400]. However, a recent study of over 92,000 patients followed in the National Health Service (UK) showed a significant (9.8%) rate of complications using a more broad definition and following patients for a longer period of time [401]. The level of detail regarding the precise nature of complications in this paper was poor. These findings suggest that, as with any SUI surgery, MUS surgery can be associated with complications and fully informed consent is mandatory. In general, the available published evidence would suggest that MUS do not seem to be associated with significantly higher rates of morbidity and complications compared to other surgeries for SUI such as open retropubic colposuspension. Pelvic organ prolapse is more common after colposuspension whilst voiding dysfunction occurs more often after MUS [368]. The ESTER review has commented that the level of detail regarding short-to-medium adverse event data is poor for all SUI surgeries [363] and the Panel is aware of the recent findings from the Independent Medicines and Medical Devices Safety Review in the UK which has raised the possibility that the level of complications from synthetic MUS may be higher than the medical literature would suggest [361]. The ESTER systematic review included seven studies comparing re-intervention after transobturator MUS and retropubic MUS [363]. Pooled analysis of these studies showed wide CIs and considerable uncertainty around the estimated OR (12-month post-surgery: OR: 1.37). At 12 to 60 months after the procedure, rates of repeat continence surgery were considerably higher in women undergoing transobturator MUS (18.3%) compared with retropubic MUS (0.5%), although only two studies were available for the analysis. A similar trend was observed in studies with a longer follow-up period (> 60 months) but the pooled analysis of these studies showed wide CIs. For retropubic MUS surgery, the bottom-to-top route was 10% more efficacious than topto-bottom in terms of subjective cure and it was associated with less voiding dysfunction, bladder perforations and vaginal erosion [363]. Single-incision mid-urethral slings Although there have been many studies published on single-incision devices, it should be noted that there are significant differences in technical design between devices and it may be misleading to make general statements about them as a class of operation. It should also be noted that some devices have been withdrawn from the market (e.g. TVT Secur®, Minitape, MiniArc®), and yet evidence relating to these devices may still be included in current meta-analyses. There was evidence to suggest single-incision slings are quicker to perform and cause less post-operative thigh pain, but there was no difference in the rate of chronic pain. There was insufficient evidence for direct comparisons between single-incision slings, and no conclusions have been reached about differences between devices. The ESTER systematic review showed, based on low quality evidence, that at 12 months retropubic MUS and transobturator MUS were, on average, more effective than single-incision sling (TVT, OR: 0.50, p = 0.01 and TOT, OR: 0.68, p = 0.02). The SUCRA score was 39.8% for women cured after single-incision slings. However, since not all single-incision devices have been assessed in a comparative RCT, it may be unsafe to assume that they are collectively technically similar or exhibit the same levels of efficacy. Complications of single-incision slings The meta-analysis results for the comparison between single-incision sling and transobturator MUS showed similar rates of mesh erosion or extrusion between interventions (4.8% vs. 3.7%; OR: 1.23). Rates of ‘postoperative pain’ were higher after retropubic MUS than after single-incision slings (19.2% vs. 6.8% OR: 0.21).

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The rate of unspecified pain was higher after transobturator MUS than after single-incision sling both at twelve months (1.0% vs. 5.2%, OR: 0.24) and at 24 months (1.4% vs. 10.4%, OR: 0.16). Single-incision sling was associated with more repeat surgeries compared with transobturator MUS (5.1% vs. 2.9%, OR: 1.57). At over 36 months after the procedure, the repeat surgery rate was 10.3% for single-incision slings vs. 7.6% for transobturator MUS (OR: 1.42) [363]. Sexual function after synthetic mid-urethral sling surgery A systematic review examining the effect of synthetic MUS on female sexual function suggested different and contradictory results between studies. Overall, more papers show an improvement, or no change, in sexual function because of a reduction in coital incontinence, anxiety and avoidance of sex. Dyspareunia was the most common cause of worsening of sexual function and the precise incidence is difficult to estimate as a lot of studies do not report it [402]. A meta-analysis of outcome measures in trials of sling procedures suggests that single-incision slings are associated with a significantly higher improvement in sexual function compared to standard MUS procedures [403]. 4.2.4.3.2.4.1 Summary of evidence and recommendations for mid-urethral slings Summary of evidence The retropubic MUS appears to provide better patient-reported subjective and objective cure of SUI, compared with colposuspension. Mid-urethral synthetic slings inserted by either the transobturator or retropubic route provide equivalent patient-reported outcomes at one year. Mid-urethral synthetic slings inserted by the retropubic routes have higher patient-reported cure rates in the longer term. Long-term analyses of MUS cohorts showed a sustained response beyond ten years. The retropubic route of insertion is associated with a higher intra-operative risk of bladder perforation and a higher rate of voiding dysfunction than the transobturator route. The transobturator route of insertion is associated with a higher risk of groin pain than the retropubic route. Long-term analysis of MUS showed no difference in terms of efficacy for the skin-to-vagina (outsidein) compared to vagina-to-skin (inside-out) directions up to nine years. The top-to-bottom (inside-out) direction in the retropubic approach is associated with a higher risk of post-operative voiding dysfunction. The comparative efficacy of single-incision slings against conventional MUS is uncertain. Operation times for insertion of single-incision MUS are shorter than for standard retropubic slings. Blood loss and immediate post-operative pain are lower for insertion of single-incision slings compared with conventional MUS. There is no evidence that other adverse outcomes from surgery are more or less likely with singleincision slings than with conventional MUS. In women undergoing surgery for SUI, coital incontinence is likely to improve. Overall, there is conflicting evidence regarding sexual function following SUI surgery. Improvement in sexual function appears higher with single-incision slings than with standard MUS.

LE 1a 1a 1b 2b 1a 1a 2a 1b 1a 1b 1b 1b 3 2a 1a

NB: Most evidence on single-incision slings is from studies using the tension-free vaginal tape secure (TVT-S) device and although this device is no longer available, it is, however, still included in many systematic reviews and meta-analyses.

Recommendations Offer a mid-urethral sling (MUS) to women seeking surgical treatment for stress urinary incontinence following a thorough discussion of the risks and benefits relative to other surgical modalities. Inform women that long-term outcomes from MUS inserted by the retropubic route are superior to those inserted via the transobturator route. Inform women of the complications associated with MUS procedures and discuss all alternative treatments in the light of recent publicity surrounding surgical mesh. Inform women who are being offered a single-incision sling that long-term efficacy remains uncertain.

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4.2.4.3.2.5 Other treatments for uncomplicated SUI Intravesical balloon treatment has been explored for women with SUI. The Vesair® gas-filled intravesical balloon differs from other SUI treatment modalities in that it is not intended to increase outlet resistance or minimise urethral hypermobility but to attenuate the fluctuation of intravesical pressure when the abdominal pressure increases [404, 405]. Two sham-controlled randomised trials evaluating the Vesair® intravesical balloon have been published so far [404, 406]. Both reported significant reductions in incontinence symptoms and pad weight but QoL was not significantly different between study arms. High levels of adverse events were reported in both trials as well as significant numbers of withdrawals/device removals. The most common adverse events were dysuria, urgency, gross haematuria and UTIs. Mechanical devices have been used to treat SUI for centuries. There are several devices available which act either by supporting the bladder neck or urethra to address urethral hypermobility, or by occluding the urethral lumen. A 2014 Cochrane systematic review of eight RCTs that included three small trials comparing mechanical devices to no treatment found inconclusive evidence of benefit [407]. Another 2014 review of mechanical devices concluded that there was insufficient evidence to support their use in women [408]. The place of mechanical devices in the management of SUI remains in question. Currently there is little evidence from controlled trials on which to judge whether their use is better than no treatment and large well-conducted trials are required for clarification. There was also insufficient evidence in favour of one device over another and little evidence to compare mechanical devices with other forms of treatment [407]. Systematic reviews regarding compression devices such as the adjustable compression therapy and artificial urinary sphincter devices have published evidence to support their use [409, 410]. Although these procedures are largely reserved for those with recurrent or complicated SUI (see Section 4.2.4.3.3.3 - External compression devices) these recent additions to the literature include the use of some compression devices for uncomplicated SUI. 4.2.4.3.2.5.1 Summary of evidence and recommendations for other treatments for uncomplicated SUI Summary of evidence Vesair® intravesical pressure-attenuating balloon improves SUI compared to sham control at three months. Vesair® intravesical pressure-attenuating balloon is associated with significant levels of adverse events. Implantation of an artificial sphincter can improve or cure incontinence in women with uncomplicated SUI. Implantation of the adjustable compression therapy (ACT©) device may improve uncomplicated SUI. Complications, mechanical failure and device explantation often occur with both the artificial sphincter and the ACT©. Recommendations Offer Vesair® intravesical balloon to women with mild-to-moderate stress urinary incontinence (SUI) who failed conservative treatments only as part of a well-conducted research trial. Offer mechanical devices to women with mild-to-moderate SUI who failed conservative treatments only as part of a well-conducted research trial. Inform women receiving artificial urinary sphincter or adjustable compression device (ACT©) that although cure is possible, even in expert centres there is a high risk of complications, mechanical failure or a need for explantation.

LE 1b 1b 3 3 3

Strength rating Weak

Strong Strong

4.2.4.3.3 Surgery for women with complicated stress urinary incontinence This section will address surgical treatment for women with complicated SUI as defined in Section 4.2.2 Classification above. Neurogenic LUT dysfunction is reviewed by the EAU Guidelines on Neuro-Urology [9]. Women with associated genitourinary prolapse are included in Section 4.7 - Pelvic organ prolapse and LUTS. The principal procedures included are: • Colposuspension or MUS (synthetic or autologous) following failed primary SUI surgery; • External compression devices: adjustable compression therapy (ACT©) and artificial urinary sphincter (AUS); • Adjustable slings.

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4.2.4.3.3.1 Colposuspension or sling (synthetic or autologous) following failed primary SUI surgery Urinary incontinence following SUI surgery may indicate persistent or recurrent SUI, or the development of de novo UUI, or both. Careful evaluation including urodynamics is an essential part of the work-up of these patients. Most of the data on surgery for SUI refer to primary operations. Even when secondary procedures have been included, it is unusual for the outcomes in this subgroup to be separately reported. When they are, the numbers of patients is usually too small to allow meaningful comparisons. This means that no firm recommendations can be made regarding which modality is best for the treatment of recurrent SUI and previous systematic reviews have commented that in view of the absence of any evidence, clinicians must rely largely on expert opinion or personal experience when advising patients about treatment options [411]. The ESTER network meta-analysis revealed that women with transobturator MUS were more likely to undergo re-do surgery than those who had retropubic MUS and in general fewer repeat surgeries were observed after retropubic MUS compared with other interventions [363]. A recent update of two Urinary Incontinence Treatment Network trials [412] compared the re-treatment-free survival rates by initial surgical procedure. Five-year re-treatment-free survival rates (and standard errors) were 87% (3%), 96% (2%), 97% (1%), and 99% (0.7%) for Burch colposuspension, autologous fascial sling, transobturator, and retropubic MUS groups respectively (p < 0.0001). Types of surgical re-treatment included autologous fascial sling (19), bulking agent (18), and synthetic sling (1). This suggests that MUS, may not be preferred in cases of recurrent SUI [412]. In these cohorts, 6% of women after standard anti-incontinence procedures were retreated within five years, mostly with injection therapy or autologous fascial sling. Not all women with recurrent SUI chose surgical re-treatment. A 2019 Cochrane Review attempted to summarise the data regarding different types of MUS procedures for recurrent SUI after failure of primary surgical therapy [413]. The literature search identified 58 records but all were excluded from quantitative analysis because they did not meet eligibility criteria. Overall, there were no data to recommend or refute any of the different management strategies for recurrent or persistent SUI after failed MUS surgery. Another systematic review looking at the effectiveness of MUS in recurrent SUI included 12 studies and reported an overall subjective cure rate following MUS for recurrent SUI after any previous surgery of 78.5% at an average 29 months of follow-up [414]. The subjective cure rate following MUS after previous failed MUS was 73.3% at a follow-up of 16 months. The authors commented that there was a lower cure rate with transobturator compared to the retropubic tape for recurrent SUI after previous surgery. A further systematic review aimed to assess the effectiveness and complications of various surgical procedures for the treatment of female recurrent SUI and reported on data from 350 women in 10 RCTs with a mean followup of 18.1 months [415]. Conversely, the authors found no difference in patient-reported and objective cure/ improvement rates between retropubic and transobturator MUS in the setting of recurrent SUI. There was also no significant difference between Burch colposuspension and retropubic MUS in terms of patient-reported improvement or objective cure/improvement. Systematic review of older trials of open surgery for SUI suggests that the longer-term outcomes of redo open Burch colposuspension may be poor compared to autologous fascial slings [416]. Similarly, one large nonrandomised comparative series suggested that cure rates after more than two previous operations were 0% for open colposuspension and 38% for autologous fascial sling [417]. 4.2.4.3.3.1.1 Summary of evidence for surgery in those with recurrent SUI following failed primary SUI surgery Summary of evidence Failure rates of single-incision slings appear higher than with other types of MUS. The incidence of repeat surgery is higher in those women who underwent primary transobturator MUS compared to retropubic MUS. The 5-year failure rate of Burch colposuspension appears higher than for synthetic- or traditional sling procedures. Some studies suggest that retropubic synthetic MUS procedures appear to be more effective than transobturator MUS for the treatment of recurrent SUI, but this is not a consistent finding in the literature. Most procedures will be less effective when used as a second-line procedure. Burch colposuspension has similar short-term patient-reported or objective cure rates when compared to TVT for the treatment of recurrent SUI. Autologous sling appears superior to Burch colposuspension for the treatment of recurrent SUI.

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2a 1b 2b

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4.2.4.3.3.2 Adjustable slings Although adjustable slings are most commonly used as a treatment for complicated SUI, they may also be considered as a treatment for uncomplicated SUI. There are no RCTs investigating outcome of adjustable sling insertion for women with SUI. There are limited data from cohort studies on adjustable tension slings with variable selection criteria and outcome definitions. Few studies include sufficient numbers of patients or have a long enough follow-up to provide useful evidence. One adjustable sling is the Remeex system (Neomedic International®, Terrassa, Spain), which was investigated in a prospective study of 230 women with SUI [418]. After a mean follow-up of 89 months, 165 patients were cured of SUI (71.7% in the intention-to-treat [ITT] analysis, 80.5% in per protocol analysis [PP]). Forty patients remained incontinent (17.4% in ITT, 19.5% in PP). Eighty-eight patients required re-adjustment of the sling during the followup. The tension was increased in 82 cases due to recurrence of SUI and reduced in six due to outlet obstruction. However the currently available adjustable sling devices have differing designs, making it difficult to draw general conclusions about adjustable slings as a class of procedure. 4.2.4.3.3.2.1 Summary of evidence for adjustable slings Summary of evidence LE There is only low level evidence to suggest that adjustable mid-urethral synthetic sling devices may be 3 effective for cure or improvement of SUI in women. There is no evidence that adjustable slings are superior to standard MUS. 4 4.2.4.3.3.3 External compression devices External compression devices are usually used in the treatment of recurrent SUI after failure of previous surgery but can be considered as a primary treatment. Publications in the literature have largely included patients with profound intrinsic failure of the sphincter mechanism, characterised by very low VLPPs or low urethral closure pressures [409, 410]. The two intracorporeal external urethral compression devices available are the adjustable compression therapy (ACT©) device and AUS. ACT®: Using US or fluoroscopic guidance, the ACT© device is inserted by placement of two inflatable spherical balloons, one on either side of the bladder neck. The volume of each balloon can be adjusted through a subcutaneous port placed within the labia majora. A systematic review including eight studies published between 2007 and 2013 with follow-up ranging from 1-6 years revealed 15-44% of patients considered that their SUI had been cured and 66–78.4% were satisfied with the result [409]. The explantation rate ranged between 19 and 31%. In these studies a significant reduction in the number of pads used per day was consistently observed after ACT® balloon placement and QoL was significantly improved. The authors concluded that ACT® balloons constitute a reasonable, minimally-invasive alternative for the treatment of female SUI due to intrinsic sphincter deficiency, especially in patients who have already experienced failure of standard surgical treatment. AUS: The major advantage of AUS over other anti-incontinence procedures is the perceived ability to be able to void normally [407]. There are a few case series of AUS in women, including four series (n = 611), with study populations ranging from 45 to 215 patients and follow-up ranging from one month to 25 years [419-422]. Case series have been confounded by varying selection criteria, especially the proportion of women who have neurological dysfunction or who have had previous surgery. Most patients achieved an improvement in SUI, with reported subjective cure in 59–88%. Common side effects included mechanical failure requiring revision (up to 42% at ten years) and explantation (5.9–15%). In a retrospective series of 215 women followed up for a mean of six years, the risk factors for failure were older age, previous Burch colposuspension and pelvic radiotherapy [422]. Early reports of laparoscopically implanted AUS do not have sufficient patient populations and/or sufficient follow-up to be able to draw any conclusions [423, 424]. A more recent systematic review included 17 studies but all were retrospective or prospective non-comparative case series [410]. Most patients in the included trials had undergone at least one anti-incontinence surgical procedure prior to AUS implantation (69.1–100%). Outcomes revealed that complete continence rates ranged from 61 to 100%. The rates of explantation were 0–45%, erosion rates were 0–22% and mechanical failure rates were 0–44%. The authors concluded that AUS can provide excellent functional outcomes in female patients with SUI resulting from intrinsic urethral sphincter deficiency but at the cost of a relatively high morbidity.

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4.2.4.3.3.3.1 Summary of evidence for external compression devices Summary of evidence Implantation of an artificial sphincter improves or cures incontinence in women with SUI caused by sphincter insufficiency. Implantation of the artificial urinary sphincter (AUS) device may improve complicated SUI. Implantation of the adjustable compression therapy (ACT©) device may improve complicated SUI. Complications, mechanical failure and device explantation often occur with both the artificial sphincter and the ACT©. Explantation of AUS is more frequent in older women and among those who have had previous Burch colposuspension or pelvic radiotherapy.

LE 3 3 3 3 3

4.2.4.3.3.4 Recommendations for complicated stress urinary incontinence Recommendations Management of complicated stress urinary incontinence (SUI) should only be offered in centres with appropriate experience (see Section: 4.2.4.3.1). Base the choice of surgery for recurrent SUI on careful evaluation, including individual patient factors and considering further investigations such as cystoscopy, multichannel urodynamics, as appropriate. Inform women with recurrent SUI that the outcome of a surgical procedure, when used as a second-line treatment, is generally inferior to its use as a first-line treatment, both in terms of reduced efficacy and increased risk of complications. Only offer adjustable mid-urethral sling as a primary surgical treatment for SUI as part of a structured research programme. Consider secondary synthetic sling, bulking agents, colposuspension, autologous sling or artificial urinary sphincter (AUS) as options for women with complicated SUI. Inform women receiving AUS or adjustable compression device (ACT©) that although cure is possible, even in expert centres, there is a high risk of complications, mechanical failure or a need for explantation.

Strength rating Strong Strong

Weak

Strong Weak Strong

4.2.4.3.4 Surgery for stress urinary incontinence in special patient groups 4.2.4.3.4.1 Stress urinary incontinence surgery in obese women There is no agreement as to the outcome of incontinence surgery in obese women. Secondary analysis of an RCT on retropubic and transobturator tapes in the treatment of women with SUI suggests that obese women experience inferior outcome compared to non-obese women. Stratification of patients according to BMI (< 30 and ≥ 30) shows significant difference in objective dry rates (negative pad test) at one (85.6% vs. 67.8%) and five years (87.4% vs. 65.9%) and subjective cure (absence of SUI symptoms) at one (85.8% vs. 70.7%) and five years (76.7% vs. 53.6%, respectively). Between one and five years, 6.7% and 16.3% of patients initially dry (negative pad test) after surgery developed a positive pad test, respectively [425, 426]. Conversely, short-term outcome of single-incision MiniArc® sling showed comparable objective cure rates (negative cough stress test) at two years (86% and 81% in non-obese and obese women, respectively); similar improvement of the Urinary Distress Inventory 6 and Incontinence Impact questionnaire 7 was observed in non-obese and obese women [427]. 4.2.4.3.4.2 Stress urinary incontinence surgery in elderly women Age appears to be a significant factor in outcome from SUI surgery but there is conflicting evidence in the literature. An RCT of 537 women comparing retropubic to transobturator tape, showed that increasing age was an independent risk factor for failure of surgery over the age of 50 [428]. An RCT assessing risk factors for the failure of TVT vs. transobturator tension-free vaginal tape (TVT-O) in 162 women also found that age is a specific risk factor (adjusted OR: 1.7 per decade) for recurrence at one year [429]. In addition, based on a sub-analysis of a trial cohort of 655 women at 2 years follow-up, it was shown that elderly women were more likely to have a positive stress test at follow-up (OR: 3.7) were less likely to report objective or subjective improvement in stress and UUI, and were more likely to undergo re-treatment for SUI (OR: 3.9). There was no difference in time to post-operative normal voiding [430]. Another RCT comparing immediate TVT vs. no surgery (or delayed TVT) in older women, confirmed efficacy of surgery in terms of QoL and satisfaction, but with more complications in the surgical arm [431].

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Conversely, a cohort study evaluating 181 women undergoing TVT-O surgery, found that women over 70 years had similar outcomes when compared to women under 70 years old in terms of cure rates (92.5% vs. 88.3%, p = 0.40), voiding dysfunction, vaginal erosion and groin pain at a median follow-up of 24 months [432]. Furthermore, a systematic review of the efficacy of treatments of UI in older patients suggests that MUS are successful in older patients (≥ 65 years) with 5.2-17.6% reporting persistent SUI after surgery. No difference in the frequency of de novo UUI, persistent UUI and persistent SUI was found in older patients [365]. A cohort study of 256 women undergoing vagina-to-skin (inside-out) TOT reported similar efficacy in older vs. younger women, but there was a higher risk of de novo urgency in older patients [433]. 4.2.4.3.4.3 Summary of evidence and recommendations for SUI surgery in special patient groups Summary of evidence Incontinence surgery may be safely performed in obese women, however, outcomes may be inferior. The risk of failure from surgical repair of SUI, and the risk of suffering adverse events, appears to increase with age. There is no evidence that any surgical procedure has greater efficacy or safety in older women than another procedure.

Recommendations Inform obese women with stress urinary incontinence (SUI) about the increased risks associated with surgery, together with the lower probability of benefit. Inform older women with SUI about the increased risks associated with surgery, together with the likelihood of lower probability of benefit.

LE 1 2b 4

Strength rating Weak Weak

4.2.5 Follow-up The follow-up of patients with SUI will be dependent on the treatment given. For conservative and physical therapies sufficient time should be allowed for the demonstration of treatment effect. For pharmacological treatment early follow-up is recommended. For most surgical interventions short-term follow-up should be arranged to assess efficacy and identify any surgical complications in the early post-operative phase. The Panel is supportive of long-term outcome assessment via registries and recognises the paucity of highquality long-term data specifically regarding complications from surgery.

4.3

Mixed urinary incontinence

The term ‘mixed urinary incontinence’ is extremely broad because it may refer to equal stress and urgency symptoms, stress-predominant symptoms, urgency-predominant symptoms, urodynamic SUI (USUI or USI) with DO or USUI with clinical urgency symptoms, but no DO [434]. The challenge of this broad definition is that it leads to inconsistencies when evaluating treatment options and outcomes. 4.3.1 Epidemiology, aetiology and pathophysiology The prevalence rates of MUI vary widely in the literature. A large majority of epidemiological studies have either not considered subtypes of UI, or only reported on SUI, UUI and MUI. The current literature is unclear regarding the population prevalence and risks for the different UI subtypes [8]. There are a large number of urinary symptom questionnaires employed in epidemiological research all with varying evidence of validity. Caution is needed when comparing epidemiological studies that do or do not report a separate MUI subgroup, and when generalising from population level data to clinical practice. The problems arise from significant heterogeneity in terms of types of questionnaires/surveys used, population parameters, variable response rates, varying definitions of MUI, and outcome measures. It seems apparent, however, that MUI is the second most common form of UI, after SUI, with most studies reporting a 7.5–25% prevalence [8]. Furthermore, one can extrapolate that of women with UI, approximately one-third have MUI [435]. In a secondary analysis of a large clinical trial 655 women were evaluated for the presence of incontinence and their response to treatment [436]. They found that 50−90% of women fell into the category of MUI based on patient-reported answers to the Medical Epidemiologic and Social Aspects of Aging (MESA) and Urinary Distress Inventory (UDI) questionnaires. However, when objective criteria such as urodynamic findings were used, only 8% of women were categorised as having MUI.

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Mixed incontinence is usually caused by a combination of the same factors that cause stress and urgency incontinence. Several factors may be responsible for its development, including oestrogen deficiency, abnormalities in histomorphology, and microstructural changes [437]. One report postulates that an incompetent sphincter and bladder neck allows urine to enter the proximal urethra during stress, causing a urethro-detrusor reflex that triggers an involuntary detrusor contraction, which then causes urgency and UUI [438]. Another paper also showed that urine flow across urethral mucosa led to an increase in the excitability of the micturition reflex [439]. Ultimately, it is likely that one theory or risk factor does not explain the development of MUI and its symptoms; it is more probable that disturbances in several elements and the inability of the bladder to compensate results in the development of MUI [437]. 4.3.2 Diagnostic evaluation Assessment of patients with MUI begins with a thorough history of the patient’s urinary symptoms and follows the recommendations set out in the general evaluation and diagnosis of LUTS section. It is conventional to try and categorise MUI as either stress or urge predominant. Mixed UI is difficult to diagnose, as the condition comprises many phenotypes. Some women exhibit detrusor contractions provoked by physical stressors, some have unprovoked detrusor contractions, and many have no abnormal detrusor contractions, but still report urine leakage with the sensation of urgency. Some women with urgency symptoms do not manifest UUI because their urethral sphincter is strong and often able to prevent urine leakage [440]. The role of urodynamics in MUI is unclear, but establishing objective degrees of SUI and DO incontinence may help in counselling patients about the most appropriate initial treatment option. 4.3.2.1

Summary of evidence and recommendations for the diagnosis of mixed urinary incontinence

Summary of evidence There is no evidence that urodynamics affects outcomes of treatment for MUI.

Recommendations Complete a thorough history and examination as part of the assessment of mixed urinary incontinence (MUI). Characterise MUI as either stress-predominant or urgency-predominant where possible. Use bladder diaries and urodynamics as part of the multi-modal assessment of patients with MUI to help inform the most appropriate management strategy.

LE 3

Strength rating Strong Weak Strong

4.3.3 Disease Management 4.3.3.1 Conservative management Women with MUI generally have more severe symptoms and respond less well to treatment than women with only SUI or UUI [441]. Clinicians are encouraged to begin treatment for MUI with conservative management directed toward the most bothersome component of the woman’s symptom spectrum and to reserve surgery as a last resort [440]. 4.3.3.1.1 Pelvic floor muscle training in mixed urinary incontinence An RCT comparing PFMT with and without an audiotape for 71 women with UI did not find any difference between the two treatment arms [442]. Mean number of incontinent episodes per day decreased from 3.9 overall to 3.2 for participants with MUI. Six months after completing the course of exercises approximately one third of all enrolees reported that they continued to note good or excellent improvement and desired no further treatment. A small RCT including 34 women with SUI and MUI compared 8 weeks of PFMT with no treatment and found that PFM training significantly increased PFM strength, improved QoL, and reduced the frequency of UI episodes compared to no treatment [443]. Another RCT including SUI and MUI confirmed these results [444]. A multicentre randomised controlled non-inferiority trial on 467 women with MUI was conducted in 10 hospitals. Participants were randomised 1:1 to receive electro-acupuncture (36 sessions over 12 weeks with 24 weeks of follow-up) or PFMT-solifenacin (5 mg/day) over 36 weeks. In women with moderate-to-severe MUI, electro-acupuncture was not inferior to PFMT-solifenacin in decreasing the 72-hour incontinence episodes (between-group difference, -1.34%) [445].

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In a comparative study of the effectiveness of behavioural and PFMT (combined with MUS vs. sling alone in women with MUI, 416 (86.7%) had post-baseline outcome data and were included in primary 12-month analyses [446]. The UDI score in both groups significantly decreased (178.0 to 30.7 points in the combined group, 176.8 to 34.5 points in the sling-only group). The model-estimated between-group difference did not meet the minimal clinically important difference threshold. Adherence to the behavioural and PFMT regimes, which is a prerequisite for achieving effect, was not reported in the study. A Cochrane review comparing PFMT with no or sham treatment included 31 RCTs from 14 countries, but there was only one study including women with MUI and one with UUI and none of them reported data on cure, improvement, or number of episodes of these subgroups [325]. Another Cochrane review comparing different approaches to delivery of PFMT (21 RCTs) concluded that increased intensity of delivery of the therapy improves response and that there is no consistent difference between group therapy and individualised treatment sessions [329]. This concurs with the latest ICI publication [331]. No other consistent differences between techniques were found. The effect of combining biofeedback with PFMT has already been fully addressed in SUI Section 4.2.4.1.3 - Pelvic floor muscle training and there was no evidence of any additional benefit in a population with predominantly MUI. 4.3.3.1.2 Bladder training Details on bladder training programs are elucidated in Section 4.2.4 (SUI). The ICI 2017 [331] concluded that for women with UUI or MUI, PFMT and BT are effective first-line conservative therapies. One RCT assigned 108 women with diagnoses of SUI (n = 50), UUI (n = 16), or MUI (n = 42) to six weeks of BT and PFMT or BT alone [447]. The results showed that overall, and in the SUI and MUI subgroups, significantly more patients in the BT and PFMT group reported cure and improved symptoms. 4.3.3.1.3 Electrical stimulation A Cochrane review on ES for SUI included participants with SUI or stress-predominant MUI. Twenty-five percent of the included trials were deemed to have a high risk of bias due to a variety of factors including baseline differences between groups and industry funding. For subjective cure or improvement of SUI, lowquality evidence indicated that ES was better than no active treatment (RR: 1.73), or sham treatment (RR: 2.03). Electrical stimulation for OAB and SUI is covered in Sections 4.1.4.1.5.4 and 4.2.4.1.3.2, of the respective topics. 4.3.3.2

Summary of evidence and recommendations for conservative management in MUI

Summary of evidence Pelvic floor muscle training appears less effective for MUI than for SUI alone. Pelvic floor muscle training is better than no treatment for improving UI and QoL in women with MUI. Bladder training, combined with PFMT, may be beneficial in the treatment of MUI.

Recommendations Treat the most bothersome symptom first in patients with mixed urinary incontinence (MUI). Offer bladder training as a first-line therapy to adults with MUI. Offer supervised intensive pelvic floor muscle training, lasting at least three months, as a first-line therapy to all women with MUI (including elderly and postnatal women).

LE 2 1a 1b

Strength rating Weak Strong Strong

4.3.3.3 Pharmacological management Many RCTs include patients with MUI with predominant symptoms of either SUI or UUI but few report outcomes separately for those with MUI compared to pure SUI or UUI groups. 4.3.3.3.1 Tolterodine In an RCT of 854 women with MUI, tolterodine ER was effective for improvement of UUI, but not SUI suggesting that the efficacy of tolterodine for UUI was not altered by the presence of SUI [448]. In another study (n = 1,380) tolterodine was equally effective in reducing urgency and UUI symptoms, regardless of whether there was associated SUI [449]. Similar results were found for solifenacin [450, 451].

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4.3.3.3.2 Duloxetine In one RCT of duloxetine vs. placebo in 588 women, subjects were stratified into either stress-predominant, urgency-predominant or balanced MUI groups. Duloxetine was effective for improvement of incontinence and QoL in all subgroups, although results in stress-predominant groups were better [452]. Treatment-emergent adverse event rate in the duloxetine group was high at 61.3% with discontinuation rates of 15.7%. Adverse event rates were higher in those participants taking other concomitant anti-depressant agents. Duloxetine was also found to have equal efficacy for SUI and MUI from an RCT (n = 553) following secondary analysis of respective subpopulations [453]. No data on adverse events was reported in this study. 4.3.3.3.3 Summary of evidence and recommendations for pharmacological management of MUI Summary of evidence Limited evidence suggests that anticholinergic drugs are effective for improvement of the UUI component in patients with MUI. Duloxetine is effective for improvement of both SUI and MUI symptoms, but adverse event rates are high.

Recommendations Treat the most bothersome symptom first in patients with mixed urinary incontinence (MUI). Offer anticholinergic drugs or beta-3 agonists to patients with urgency-predominant MUI. Offer duloxetine (where licensed) to selected patients with stress-predominant MUI unresponsive to other conservative treatments and who want to avoid invasive treatment, counselling carefully about the risk of adverse events.

LE 2 1b

Strength rating Weak Strong Weak

4.3.3.4 Surgical management The surgical treatment options for MUI include all the anti-incontinence procedures outlined in the SUI chapter. Many RCTs include both patients with pure SUI or pure UUI as well as patients with MUI. However, very few RCTs report separate outcomes for MUI subgroups. Post-hoc analysis of a large RCT showed that in women undergoing either autologous fascial sling or Burch colposuspension, the outcomes were poorer for women with a concomitant complaint of pre-operative urgency [430]. A similar post-hoc review of another RCT comparing transobturator and retropubic MUS showed that the greater the severity of pre-operative urgency, the more likely that treatment would fail [99]. However, an earlier study had found that surgery provided similar outcomes, whether or not urgency was present prior to surgery (this study included only a few patients with urodynamic DO). Another RCT including 93 patients with MUI showed a statistical improvement in continence and QoL in the group that had TVT and Botox® rather than with either treatment alone [454]. Case series tend to show poorer results in patients with MUI compared with those with pure SUI. In a case series of 192 women undergoing MUS insertion, overall satisfaction rates were lower for women with mixed symptoms and DO on pre-operative urodynamics compared to those with pure SUI and normal urodynamics (75% vs. 98%, respectively) [455]. A comparison of two parallel cohorts of patients undergoing Burch colposuspension for SUI, with and without DO, found inferior outcomes in women with MUI [456]. One cohort of 450 women, showed that in urgency-predominant MUI, the success rate of TVT fell to 52% compared to 80% in stress-predominant MUI [457]. In a study with 1,113 women treated with TVT-O, SUI was cured equally in stress-predominant MUI or urgency-predominant MUI. However, women with stresspredominant MUI were found to have significantly better overall outcomes than women with urgency predominant MUI [458]. In contrast to studies examining older surgical methods, more recent studies (generally small case series) reported that UUI symptoms improve in 30% to 85% of women with MUI after MUS surgery [459]. In a prospective, multicentre, comparative trial 42 women who had a TVT for MUI had a greater improvement in urgency and QoL scores than 90 women who had a TOT. There were no significant differences in the cure and satisfaction rates between the two groups [460].

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In a single-centre prospective study, 86 consecutive women underwent TOT for MUI. At a mean follow-up of 59 months, SUI was cured objectively in 83.7% and subjectively in 87.2% of the patients. The continence rates were 74.4% for UUI and 66.3% for MUI (cure of both components). The patient-reported success rate was 87.2% (‘much better’ or ‘very much better’ on Patient Global Impression of Improvement scale). There were statistically significant improvements in all domains except general health. The univariate analysis found no significant risk factor for persistence of SUI. Median age > 60 years and menopause were predictive for persistence of UUI. Median and mean age > 60 years were predictive of persistence of overall incontinence [461]. Overall, the outcome for women with pre-existing UUI remains uncertain. In a secondary analysis of a study of transobturator TVTs in the treatment of women with urodynamic MUI, no difference in patient-reported success rates was found between the vagina-to-skin (inside-out) and the skin-tovagina (outside-in) groups (63.2% and 65.5%, respectively; OR: 1.11, 95% CI: 0.33–3.70, p > 0.999) at 9 years follow-up [399]. Analysis of the trial populations included in the meta-analysis on single-incision slings suggests that the evidence is generalisable to women who have predominantly SUI, and no other clinically severe LUT dysfunction. The evidence is not adequate to guide choice of surgical treatment for those women with MUI, severe POP, or a history of previous surgery for SUI. In general research trials should define accurately what is meant by MUI. There is a need for well-designed trials comparing treatments in populations with MUI, and in which the type of MUI has been accurately defined. 4.3.3.4.1 Summary of evidence and recommendations for surgery in patients with MUI Summary of evidence Women with MUI are less likely to be cured of their UI by SUI surgery than women with SUI alone. The response of pre-existing urgency symptoms to SUI surgery is unpredictable.

Recommendations Treat the most bothersome symptom first in patients with mixed urinary incontinence (MUI). Warn women that surgery for MUI is less likely to be successful than surgery for stress urinary incontinence alone. Inform women with MUI that one single treatment may not cure urinary incontinence; it may be necessary to treat other components of the incontinence problem as well as the most bothersome symptom.

4.4

LE 1b 3

Strength rating Weak Strong Strong

Underactive bladder

Underactive bladder is a common clinical entity, defined by the ICS as ‘a symptom complex characterised by a slow urinary stream, hesitancy, and straining to void, with or without a feeling of incomplete bladder emptying sometimes with storage symptoms’ [462]. Diagnosis of UAB is made based on clinical symptoms and can have a highly variable presentation and aetiology. This differs from DU, which is a diagnosis based on urodynamic studies. Detrusor underactivity is defined by the ICS as ‘‘a detrusor contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or failure to achieve complete bladder emptying within a normal time span’’[1]. Acontractile detrusor is specified when there is no detrusor contraction. Female voiding dysfunction is defined by the ICS as a diagnosis based on symptoms and urodynamic investigations characterised by abnormally slow and/or incomplete micturition, based on abnormally slow urine flow rates and/or abnormally high PVR, ideally on repeated measurement to confirm abnormality. Pressure-flow studies can be required to determine the cause of the voiding dysfunction [28]. 4.4.1 Epidemiology, aetiology, pathophysiology 4.4.1.1 Epidemiology Underactive bladder as an entity remains difficult to study in part because its corresponding urodynamic correlate, “detrusor underactivity” remains loosely defined, leading to significant variability in diagnostic criteria across research studies and significant overlap of symptoms with other conditions. As a consequence of the variability in definition, reported prevalence also varies and ranges from 12% to 45% in females with increased prevalence seen with age [76] and in institutionalised elderly women [463]. MANAGEMENT OF NON-NEUROGENIC FEMALE LOWER URINARY TRACT SYMPTOMS (LUTS) - 2021

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Several studies have demonstrated similar prevalence rates for DU in the ambulatory setting of around 12%–19.4% [464-466]. As would be expected, voiding symptoms consistent with UAB are slightly higher. A Detroit population study surveyed 291 women with 20% reporting difficulty with emptying their bladder [467]. In a large cross-sectional, population-based internet survey conducted in the USA, UK and Sweden including 15,861 women ≥ 40 years, 20.1% referred to weak flow, 27.4% to incomplete bladder emptying and 38.3% to terminal dribbling [5]. Some studies have identified the coexistence of DO during filling and DU in the voiding phase of urodynamic studies (formerly known as DHIC, “detrusor hyperactivity with impaired contractility”) as a common finding in elderly women. Up to 38.1% of incontinent institutionalised women showed DHIC in urodynamic studies [468, 469]. 4.4.1.2 Aetiology The presence of DU in diverse clinical groups suggests a multifactorial aetiology [470]. Idiopathic DU is probably in part an age-dependent decrease in detrusor contractility with no other identifiable causes, but young women can also be identified as having DU. There are many secondary causes of DU including neurogenic (multiple sclerosis, multiple systemic atrophy, spinal cord injury, spina bifida, Parkinson, hydrocephalus, transverse myelitis, stroke, Guillain-Barré syndrome, diabetes mellitus, pelvic nerve injury, etc.), myogenic (acute prolonged bladder overdistension, diabetes mellitus, BOO) and iatrogenic (pelvic surgery) [471]. 4.4.1.3 Pathophysiology There are many pathways involved in normal detrusor contraction, and there are different possible sites of dysfunction [76] with a variety of mechanisms involved in UAB: • Central circuits and centres (prefrontal cortex, PAG, PMC, hypothalamus): failure of integration or processing; • Efferent pathways (sacral cord, sacral nerves, pelvic nerves, postganglionic neurons): impaired activation of detrusor; • Afferent pathways (peripheral afferent nerves, anterolateral white column, posterior column): early termination of voiding reflex; • Muscle (detrusor myocyte, extracellular matrix): loss of intrinsic contractility. Different aetiologies can share common pathophysiological mechanisms: for example, diabetes mellitus affects mainly afferent pathways and the detrusor muscle; and neurogenic diseases affect central circuits and efferentafferent pathways. One study suggests that in patients with DU, there is significant urothelial dysfunction, increased sub-urothelial inflammation and apoptosis, and altered sensory protein expression [472]. Impaired urothelial signalling and sensory transduction pathways may reflect part of the pathophysiology of DU. Pelvic ischaemia is another proposed mechanism of DU in ageing patients [472]. See Figure 1.

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Figure 1: Management and treatment of women presenting with urinary incontinence

Site of dysfunction

Major aetiological factors

Brain circuits Pontine micturition center Periaqueductal gray Limbus Hypothalamus Prefrontal cortex

Efferent pathways Sacral cord Sacral nerves Pelvic nerves Postganglionic neurons

Mechanisms

Failure of integration or processing

Impaired activation of detrusor

Neurological disease or injury Normative ageing

Afferent pathways Peripheral afferents Anterolateral white column Posterior column

Early termination of voiding reflex

Bladder outlet obstruction Diabetes mellitus

Detrusor muscle Detrusor myocite Extracellular matrix

Loss of intrinsic contractility

*Figure reproduced with permission from the publisher, from Osman N. et al., [473]. 4.4.2 Classification There is no current classification system of UAB. Patients can be classified according to presumed aetiology or pathogenic mechanism, but without sufficient longitudinal data or high-level evidence to establish prognostic factors, the classification of UAB patients in terms of relevant clinical characteristics or risk of complications is not possible. 4.4.3 Diagnostic evaluation 4.4.3.1 Symptoms associated with detrusor underactivity A retrospective study correlated LUTS with urodynamic findings in 1,788 patients (1,281 women). In women with DU (defined as PdetQmax < 20, Qmax 150 mL; in 9.6% when using PdetQmax < 30 cm H2O and Qmax < 10 mL/s; and in 6.4% when using PdetQmax < 20 cm H2O, Qmax < 15 mL/s and BVE < 90% [479]. More elaborate methods combine urodynamic data into an index or a physical quantity that reflects bladder contraction strength. A value below a certain threshold would thus diagnose DU. Again, there is no consensus regarding what is normal and what is abnormal. Table 4 provides an overview of the best-known parameters, their background and typical values. The parameter Watt’s factor (WF) estimates the power generated by the detrusor per unit area of bladder surface [480]. Its value varies during voiding. Usually, its maximum value WFmax is considered. Alternatively, its value at Qmax can be used. Projected isovolumetric pressure (PIP) is a gross simplification of the bladder output relation and estimates the maximum detrusor pressure that can be generated by the bladder when the outlet is closed, the isovolumetric detrusor pressure. The bladder contractility index (BCI) is simply a reduction of PIP to an index [46]. The population in which PIP and BCI were developed mainly consisted of males. Projected isovolumetric pressure (PIP1) also estimates the isovolumetric detrusor pressure, but was developed in an entirely female population via an experimental method [481]. A third method of quantifying bladder contraction strength involves “stop tests”. One study compared 3 types of direct measurement of the isovolumetric pressure: (i) the voluntary stop test, in which the patient voluntarily interrupts flow, (ii) the mechanical stop test, in which flow is interrupted by a balloon catheter, and (iii) the continuous occlusion test, in which the subject tries to void against a blocked outlet. The latter had the best reliability and best detected drug-induced changes. The results of the mechanical stop test were however very similar [482]. All parameters discussed above give some information on the strength of the detrusor contraction in a given void. They do not necessarily reflect what the detrusor might potentially achieve under optimum conditions [483]. Also, they give no information on another important aspect of a voiding contraction, namely its duration. No parameters for this are available. Finally, in a given patient an abnormally low bladder contraction strength does not necessarily imply an insufficient bladder contraction strength to achieve optimal voiding. Table 4 summarises different parameters to measure detrusor contraction in female patients. Table 4: Most used parameters to measure detrusor contraction in female patients Parameter Watt’s factor [480]

Basis Hill equation of muscle contraction in a spherical organ, with fixed constants obtained from experimental and clinical studies

Population 8 asymptomatic female volunteers aged 28-45 years (median 34 years)

Values Ideal voiding (bell-shaped flow curves): WFmax 11-24 W/m2 Non-ideal voiding: WFmax 5-10 W/m2 Normally WFmax > 7 W/m2 (expert opinion, unspecified population) [484] Projected isovolumetric Bladder Output Relation, Unspecified population, Classification based on expert detrusor pressure (PIP, simplified to a straight line mainly men with BPO opinion: with fixed slope of 5 cm cm H2O) and Bladder > 150: strong contraction 100-150: normal contraction Contractility Index (BCI, H2O/mL/sec (Formula: 50-100: weak contraction using PIP as an index) PdetQmax + 5xQmax) < 50: very weak contraction [46, 485] Projected isovolumetric Comparison of Qmax and 5th-95th percentile: 29-78 cm 100 women with UUI detrusor pressure PdetQmax values with stop aged 53-89 (mean: 70) H2O (PIP1, cm H2O) [481] years test results Mean: 49 cm H2O (Formula: pdetQmax + Qmax) Median: 48 cm H2O Proposed typical values: 30-75 cm H2O Mean ± SD: 48.7 ± 24.4 cm 70 women with UUI Continuous occlusion Direct measurement of aged 53-89 (mean: 70) H2O test [482] isovolumetric voiding years contraction

BPO = benign prostatic obstruction; PdetQmax = detrusor pressure at maximum flow rate; PIP = projected isovolumetric pressure; Qmax = maximum flow rate; SD = standard deviation; UUI = urgency urinary incontinence; WF = Watt’s factor.

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4.4.4 Disease management As there are so many different possible causes and pathogenic mechanisms involved in female UAB, preventive and therapeutic strategies are difficult to define. Among preventive strategies, early recognition after major surgery or labour might prevent long-term problems associated with prolonged bladder over-distension. Nerve-sparing techniques for radical pelvic surgery are more favourable in terms of early recovery of bladder function [486, 487]. Treatment of female DU includes strategies to ensure bladder drainage, increase bladder contraction, decrease urethral resistance or a combination [484]. The goals of management of UAB are to improve symptoms and QoL, to reduce the risk of complications for impaired bladder emptying, but also to identify situations where interventions may not be appropriate. 4.4.4.1 Conservative management 4.4.4.1.1 Behavioural interventions Regular or timed voiding to avoid bladder over-distension should be encouraged in women with impaired bladder sensations. Assisted voiding by abdominal straining with adequate relaxation of the PFM has been recommended, as well as double or triple voiding in an attempt to improve bladder emptying. None of these manoeuvres have proven their efficacy in a randomised study. There is a possible association between voiding by excessive abdominal straining and the risk of POP development [488]. A small retrospective study in women with neurogenic acontractile detrusor secondary to spina bifida showed that Valsalva voiding may increase the risk of rectal prolapse compared with CISC [489]. 4.4.4.1.2 Pelvic floor muscle relaxation training with biofeedback There are no RCTs on PFM relaxation training in female adults with UAB. Contradictory to common beliefs, one study found significant relaxation of the PFM after a contraction [490] and a second study found that PFMT over time increased the speed of PFM relaxation after a single contraction [491]. However, muscle contraction is known to be followed by relaxation. There is, however, some evidence from the paediatric literature including one randomised study that compared efficacy of PFM relaxation with biofeedback plus a combined therapy (including hydration, scheduled voiding, toilet training and diet) vs. combined therapy alone in children with non-neuropathic UAB and voiding dysfunction. Mean number of voiding episodes was significantly increased in the relaxation training group compared with the group with only combined treatment (6.6 ± 1.6 vs. 4.5 ± 1 times a day, p < 0.000). Post-void residual volume and voiding time decreased considerably, whereas maximum urine flow increased significantly in the relaxation group compared with the combined treatment group (17.2 ± 4.7 vs. 12.9 ± 4.6 mL/s, p < 0.01) [492]. 4.4.4.1.3 Clean intermittent self-catheterisation See Section 4.1.4.1.3 for details on CISC. 4.4.4.1.4 Indwelling catheter Indwelling urinary catheter may be an option for some women who have failed all other treatments and are unable to perform CISC. Complications include UTI, stone formation and urethral damage. Suprapubic catheterisation may be preferable over urethral catheterisation to minimise the risk of urethral trauma and pain [493]. 4.4.4.1.5 Intravesical electrical stimulation Intravesical electrical stimulation (IVES) can be used to improve bladder dysfunction by stimulating A-delta mechanoreceptor afferents, but requires preservation of afferent circuit and healthy detrusor muscle. One retrospective study in 16 patients (11 female) found that two-thirds of patients with a weak detrusor after prolonged bladder overdistension regained balanced voiding after IVES due to detrusor reinforcement [494]. 4.4.4.1.6 Intraurethral insert The intraurethral insert is a short silicone catheter containing an internal valve and pump mechanism positioned in the female urethra. See BOO Section 4.5 for more information. 4.4.4.2 Pharmacology management 4.4.4.2.1 Parasympathomimetics Theoretical approaches to UAB pharmacological treatment include direct stimulation of detrusor cells muscarinic receptors using agonists like carbachol or bethanechol, or inhibiting acetylcholinesterase (enzyme that inhibits the endogenous muscarinic agonist acetylcholine) using agents such as distigmine, pyridostigmine or neostigmine.

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A systematic review on the use of parasympathomimetics in patients with UAB included 10 RCTs (controls typically received placebo or no treatment). While three studies reported statistically significant improvements relative to control group, six did not and one even reported significant worsening of symptoms. There was no evidence for differences between individual drugs, specific uses of such drugs, or in outcome measures [495]. The review concluded that the available studies do not support the use of parasympathomimetics for treating UAB, especially when frequent and/or serious possible side-effects (gastrointestinal upset, blurred vision, bronchospasm and bradycardia) are taken into account. 4.4.4.2.2 Alpha-blockers In order to improve bladder emptying, decreasing outlet resistance through sympathetic blockade at the bladder neck/urethra has been investigated. One prospective study with tamsulosin showed similar improvement in terms of uroflowmetry parameters (specifically in the percentage of patients who had a good therapeutic response) in both women with BOO and women with DU (39.4% and 32.7% respectively) [496]. Another longitudinal study including 14 women with DU showed clinical and urodynamic improvements after tamsulosin [497]. A prospective single-blind randomised study in female patients with DU compared efficacy of alpha-blocker, cholinergic drugs or combination therapy, with the latter exhibiting the best results [498]. 4.4.4.2.3 Prostaglandins Prostaglandins are prokinetic agents that promote smooth muscle contraction. Prostaglandin E2 and F2 have been used intravesically to treat urinary retention after surgery in several studies. A Cochrane systematic review showed a statistically significant association between intravesically administered prostaglandin and successful voiding among post-operative patients with urinary retention (RR: 3.07). However, the success rate is relatively low (32%) compared to placebo. It should also be noted that the 95% CI was very wide, RCTs included in the pooled analysis were underpowered with methodological limitations, and the event rate was very low indicating a very low certainty of the evidence [499]. Intravesical prostaglandin treatment is rarely used and further research is necessary before it can be taken up more widely. 4.4.4.3 Surgical management 4.4.4.3.1 Sacral nerve stimulation Sacral nerve stimulation is an FDA approved therapy for non-obstructive urinary retention. The mechanism of action has not been fully elucidated, but activation of afferent sensory pathways, modulation-activation of central nervous system and inhibition of inappropriate activation of the guarding reflex are some of the mechanisms proposed. An RCT included 37 patients in the implantation arm and 31 in the standard medical therapy arm, showing a mean decrease in PVR volume in the implanted group compared with control of 270 mL and a mean increase in voided volume of 104 mL [500]. A meta-analysis of 7 studies showed a mean difference in PVR reduction of 236 mL and a mean voided volume increase of 299 mL [501]. The response rate during the trial phase ranged from 33–90% (mean 54.2) and the success rate of permanent implant ranged from 55–100% (mean 73.9%), highlighting that patient selection is crucial [502]. A subgroup of women with idiopathic urinary retention (Fowler’s syndrome) seem to have a higher response rate of 68-77% [503]. In conclusion, SNS is a valid option for female patients with DU, with proper patient selection. Women should have preserved bladder contractility on urodynamic tests and mechanical/anatomical BOO should be excluded. Patients with evidence of anatomical bladder outflow obstruction, suspected loss of intrinsic detrusor contractility or neurogenic bladder dysfunction show lower response rates [504]. 4.4.4.3.2 OnabotulinumtoxinA OnabotulinumtoxinA injections in external striated urethral sphincter may improve voiding in patients with DU by reducing outlet resistance and possibly reducing the guarding reflex. Some retrospective case studies show improvement in voiding symptoms, recovery of spontaneous voiding and improvement in urodynamic parameters (reduction of voiding pressure and/or urethral closure pressures, PVR) [505, 506]. The duration of symptomatic relief is short, typically three months. 4.4.4.3.3 Transurethral incision of the bladder neck Transurethral incision of the bladder neck has been described in short series of women with refractory DU. In a retrospective case study up to 40/82 (48.8%) of women achieved satisfactory outcomes (spontaneous voiding with voiding efficiency ≥ 50%), but 5 (6.1%) patients developed SUI and 2 (2.4%) developed a vesico-vaginal fistula [507].

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4.4.4.3.4 Reduction cystoplasty This is a very uncommon procedure with a few case reports described only in men [508]. 4.4.4.3.5 Myoplasty One retrospective multicentre study reported the long-term results of latissimus dorsi detrusor myoplasty in patients with bladder acontractility, with 71% recovering complete spontaneous voiding, with a mean PVR of 25 mL [509]. No other groups have published their experience to reproduce these findings. 4.4.4.4 Summary of therapeutic evidence on detrusor underactivity The level of evidence of most of therapeutic interventions on DU is low. Only CISC remains as a gold standard to reduce the adverse consequences of a high PVR and incomplete voiding, in spite of the low level of evidence that supports this statement. 4.4.4.4.1 Summary of evidence and recommendations for underactive bladder Summary of evidence Clean intermittent self-catheterisation has proven efficacy in patients who are unable to empty their bladder. Indwelling transurethral catheterisation and suprapubic cystostomy are associated with a range of complications as well as an enhanced risk of UTI. Intravesical electrical stimulation may be useful in some patients after prolonged bladder overdistension. Parasympathomimetics do not improve clinical and urodynamic parameters of UAB patients and frequent and/or serious side-effects may arise. There is limited evidence about effectiveness of alpha-blockers in women with UAB. Very low certainty evidence indicates that intravesically administered prostaglandins may promote successful voiding in patients with urinary retention after surgery. Sacral nerve stimulation improves voided volume and decreases PVR in women with DU. There is limited evidence for the effectiveness of OnabotulinumtoxinA external urethral sphincter injections to improve voiding in women with UAB. Transurethral bladder neck incision may improve voiding in women with DU, but complications (SUI, vesico-vaginal fistulae) may appear. There is very limited evidence for effectiveness of detrusor myoplasty. Recommendations Encourage double voiding in those women who are unable to completely empty their bladder. Warn women with underactive bladder (UAB) who use abdominal straining to improve emptying about pelvic organ prolapse risk. Use clean intermittent self-catheterisation (CISC) as a standard treatment in patients who are unable to empty their bladder. Thoroughly instruct patients in the technique and risks of CISC. Offer indwelling transurethral catheterisation and suprapubic cystostomy only when other modalities for urinary drainage have failed or are unsuitable. Do not routinely recommend intravesical electrical stimulation in women with UAB. Do not routinely recommend parasympathomimetics in the treatment of women with UAB. Offer alpha-blockers before more invasive techniques. Offer intravesical prostaglandins to women with urinary retention after surgery only in the context of well-regulated clinical trials. Offer onabotulinumtoxinA external sphincter injections before more invasive techniques as long as the patient is informed that the evidence to support this treatment is of low quality. Offer sacral nerve stimulation to women with UAB refractory to conservative measures Do not routinely offer detrusor myoplasty as a treatment for detrusor underactivity.

LE 3 3 3 1b 2b 1a 1b 3 3 3

Strength rating Weak Weak Strong Strong Weak Weak Strong Weak Weak Weak Strong Weak

4.4.5 Follow-up Natural history and clinical evolution at long-term follow-up of women with DU is not well known. No longitudinal cohort studies with long-term follow-up are described in the literature. The interval between followup visits will depend on patient characteristics, treatments given and the frequency of urinary complications.

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4.5

Bladder outlet obstruction

4.5.1 Introduction Bladder outlet obstruction is defined by the ICS as obstruction during voiding, characterised by increased detrusor pressure and reduced urine flow rate [1]. Its precise diagnosis requires urodynamic evaluation including an assessment of both pressure and flow. Voiding dysfunction is a broad term which is distinct from BOO and is defined by the ICS as ‘a diagnosis made by symptoms and urodynamic investigations characterised by abnormally slow and/or incomplete micturition, based on abnormally slow urine flow rates and or raised PVRs, ideally on repeated measurement to confirm abnormality’ [110]. Pressure-flow studies are required to determine the precise cause of the voiding dysfunction. Bladder outlet obstruction is one possible cause of voiding dysfunction but there are also non-obstructive causes and the two terms should not be used interchangeably. Another term that is to be differentiated from BOO and voiding dysfunction is dysfunctional voiding, which is a specific and discrete form of voiding dysfunction with an intermittent and/or fluctuating flow rate [110]. 4.5.2 Epidemiology, aetiology, pathophysiology 4.5.2.1 Epidemiology Estimates of prevalence of BOO among women vary, with figures of 2.7% to 29% reported in the literature [510]. One large series of women undergoing urodynamic evaluation for LUTS found that around 20% are diagnosed with outlet obstruction. The wide variance between studies is due to several factors, including differences in definitions and diagnostic criteria for female BOO, differences in study populations, and variation in study methodologies. The estimated prevalence rates of LUTS due to BOO in women are lower than those reported in men (18.7–18.9% vs. 24.3–24.7%), respectively [511]. Prevalence of voiding LUTS was found to be associated with age [53, 512, 513], parity [53, 514], prolapse [53, 514] and prior continence surgery [53, 514]. Bladder outlet obstruction has long been postulated to cause mainly voiding symptoms [515] but recent data from a series of 1,142 consecutive women referred for evaluation of LUT symptoms suggest that storage symptoms may be predominant in female patients diagnosed with BOO and excess daytime urinary frequency was the most common symptom reported by 69% [510]. 4.5.2.2 Pathophysiology Bladder outlet obstruction is one of multiple causes of voiding dysfunction in women. The obstruction can be either anatomical (mechanical) or functional. In anatomic BOO, there is a physical or mechanical obstruction to the outflow of urine, whereas in functional BOO there is a non-anatomic, non-neurogenic obstruction of the outlet usually resulting from non-relaxation of bladder neck, sphincter or PFM or increased urethral sphincter tone or PFM contraction during the void, as is observed in patients with dysfunctional voiding. Mechanisms for anatomic (mechanical) obstruction include external compression, fibrosis, stricture or injury to the urethra and kinking of the urethra due to POP. Progressive fibroblastic reaction around the urethra induced by mesh tapes or slings used in UI surgery may also bring about anatomic (mechanical) obstruction [471]. In a retrospective review of 192 females diagnosed with BOO, 64% had mechanical obstruction [510]. Functional obstruction, on the other hand, may be caused by failure of relaxation, or contraction, of the bladder neck and/or urethral sphincter complex or the PFMs during a sustained detrusor contraction [515]. The exact causes of this lack of relaxation, or contraction, is often elusive but might be due to sympathetic hyperactivity or hypertrophy of the bladder neck smooth muscle for primary bladder neck obstruction [516] or may be mostly behavioural as in dysfunctional voiding [517]. 4.5.2.3 Aetiology Conditions associated with anatomic BOO include POP, incontinence surgery, urethral stricture, urethral stenosis, urethral diverticulum, urethral caruncle, urethral malignancies and para-urethral masses. Conditions associated with functional BOO include primary bladder neck obstruction, dysfunctional voiding, and idiopathic urinary retention (Fowler’s syndrome). In primary bladder neck obstruction the bladder neck fails to open adequately during voiding in the absence of an anatomical obstruction [518]. It is estimated that 4.6–16% of women presenting with voiding symptoms have primary bladder neck outlet obstruction [516].

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Dysfunctional voiding is due to involuntary intermittent contractions of the peri-urethral striated or levator muscles during voiding in a neurologically normal woman, thought to be caused by faulty learned toileting behaviour [471]. There is also some evidence of a link between dysfunctional voiding and a history of sexual abuse [519]. Idiopathic urinary retention, also known as Fowler’s syndrome, is a primary disorder of the external urethral sphincter with hypertrophy of the muscle fibres, which fail to relax during micturition. It is associated with decreased detrusor contractility via enhancement of the guarding reflex. It is seen most often, but not exclusively, in young women with urinary retention and is characterised by increased urinary sphincter volume and activity/tone, which may be hormonally triggered [520]. Alpha-adrenergic agonists, such as pseudo-ephedrine commonly contained in decongestants, could lead to some form of functional obstruction due to their stimulatory effects, which may contract the bladder neck and lead to urinary retention [521]. Neurologic conditions can also bring about functional BOO in females. These will not be considered in this Guideline document and are covered elsewhere [9]. 4.5.3 Classification 4.5.3.1 Anatomic bladder outlet obstruction Anatomic BOO involves a physical or mechanical obstruction of the outflow of urine. 4.5.3.2 Functional bladder outlet obstruction Functional BOO involves a non-anatomic, non-neurogenic obstruction of the outflow of urine resulting from non-relaxation or increased tone in the bladder neck and/or urethral sphincter complex or the PFMs (Table 5). Neurologic causes of functional BOO will not be considered in this Guideline document and are covered elsewhere [9]. Table 5: Main causes of female bladder outlet obstruction Functional BOO • Primary bladder neck obstruction • Dysfunctional voiding • Idiopathic urinary retention (Fowler’s syndrome)

4.5.3.3

Anatomical BOO • Urethral stricture • Anti-incontinence surgery • Pelvic organ prolapse • Urethral diverticulum • Urethral caruncle • Urethral malignancies • Para-urethral masses

Recommendation for the classification of bladder outlet obstruction

Recommendation Strength rating Use standardised classification of bladder outlet obstruction in women (anatomical or Strong functional) and research populations should be fully characterised using such classification.

4.5.4 Diagnostic evaluation The diagnosis of BOO in women, although dependent on formal pressure flow studies, may be suggested by a number of clinical and other non-invasive assessments. 4.5.4.1 Clinical history In terms of the clinical history a range of LUTS may be elicited and these may not be confined to voiding LUTS. Women may not present until they are suffering with the possible complications of BOO such as recurrent UTI, chronic urinary retention or acute/chronic kidney disease [510]. The evidence regarding clinical utility of symptoms for the diagnosis of BOO is inconclusive. In a single-centre retrospective study involving 587 women, 38 of whom were diagnosed with BOO, the authors concluded that symptom assessment alone was insufficient for the diagnosis and a full urodynamic evaluation was essential [522]. A smaller retrospective study of 57 premenopausal women with bothersome LUTS found a significantly higher proportion of women with bladder dysfunction presenting with the symptom of UUI. Patients with voiding phase dysfunction had

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higher total scores and voiding symptom subscores in the American Urological Association Symptom Index (AUASI) [523]. Perhaps some of the difficulty in evaluating the diagnostic accuracy of urinary symptoms comes from the observation that a significant proportion of female patients presenting with obstruction will also have concomitant urodynamic abnormalities. In a large study of over 5,000 women with urinary symptoms identifying 163 with BOO additional urodynamic diagnoses were noted in 54% [524]. Similarly, in a study involving 101 women with a primary diagnosis of SUI, the prevalence of BOO (based on maximum urine flow [Qmax] of less than 12 mL per second and maximum detrusor pressure at maximum flow of more than 25 cm H2O) was 16% [525]. Symptoms alone were not sufficient to discriminate between the various different diagnostic groups of women in these 2 studies. Lower urinary tract symptoms appear to be fairly sensitive to change following intervention for BOO. A prospective study in 53 women with clinically suspected voiding dysfunction describes significant symptom improvement in 12 of 16 patients who underwent surgical intervention [526]. 4.5.4.2 Clinical examination There are no studies evaluating the clinical utility of physical examination in women with suspected BOO. Despite this it is widely considered as a key part of the medical assessment. It allows for visual inspection of the urethra and vagina for possible causes of mechanical obstruction as well as an assessment of the pelvic floor, which may be the cause of functional obstruction. 4.5.4.3 Uroflowmetry and post-void residual volume Reduced Qmax and/or incomplete bladder emptying can result from both a weakness in the contractile strength of the detrusor muscle or the presence of increased outlet resistance due to functional or anatomical/ mechanical BOO. The use of a uroflowmetry measurements to differentiate between anatomical and functional BOO was explored in a retrospective study of 157 women [517] which concluded that Qmax was statistically significantly lower in those patients with anatomical obstruction but a large degree of overlap was noted. The largest evaluation of the diagnostic utility of urine flow studies and PVR volume estimation derives from a retrospective analysis of over 1,900 patients with symptoms of voiding dysfunction of whom over 800 were diagnosed with BOO based on urodynamic assessment [527]. In this series functional BOO was over 6 times more common than anatomical/mechanical obstruction which is discordant with most of the other epidemiological literature for female BOO. The authors found that although urine flow rate alone was not accurate enough to diagnose BOO, a PVR of 200 mL or more was able to differentiate bladder neck dysfunction from the other causes of BOO, with a receiver-operator characteristics (ROC) AUC of 0.69. Conversely, in a retrospective study involving 101 women primarily presenting with SUI, a good correlation between abnormal uroflowmetry and urodynamic obstruction (phi = 0.718, p < 0.0001) was found [525]. In a prospective study of over 50 women with a clinical diagnosis of voiding dysfunction abnormal uroflow curves were observed in around 40% of women, but BOO based on pressure-flow results was confirmed in only 52% of these women [526]. 4.5.4.4 Ultrasound The major utility of US scanning in women with BOO is to detect possible complications such as bladder wall thickening or upper tract dilatation/hydronephrosis. However, the diagnostic capabilities of US have been investigated in a prospective case control study involving 27 patients with cystoscopically confirmed bladder neck obstruction [528]. The value of shear wave elastography (SWE) and acoustic radiation force impulse imaging (ARFI) in the diagnosis of female BOO was compared and the authors concluded that ARFI was more accurate than SWE, but a combination of the two techniques was superior to both in this small study. Ultrasound scanning was further evaluated in a small study of just 15 women with BOO diagnosed urodynamically [529]. The authors proposed that trans-vaginal ultrasonography was able to demonstrate a closed bladder neck during attempts at micturition and concluded that this modality was useful in the evaluation of the possible causal factors of female BOO such as primary bladder neck obstruction. 4.5.4.5 Magnetic resonance imaging The role of MRI in the diagnostic evaluation of female patients with suspected BOO is poorly defined. Although it allows for the precise anatomical evaluation of pelvic structures there are no reports describing its clinical utility in the diagnosis of female BOO. Magnetic resonance imaging in patients with urethral stricture disease can determine the degree of peri-urethral fibrosis, although the prognostic and clinical significance of such finding has not been established [530]. 4.5.4.6 Electromyography Electromyography (EMG) has been most extensively studied in the subgroup of women with BOO due to idiopathic urinary retention caused by a high-tone non-relaxing sphincter (Fowler’s syndrome). Abnormal EMG activity may be associated with non-relaxation of the striated sphincter, abnormally high urethral pressure, and,

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through an exaggerated guarding reflex, poor bladder sensation and reduced detrusor contractile strength [519, 531]. Complex repetitive discharges and decelerating bursts are specific EMG abnormalities that have been described in patients with high-tone non-relaxing sphincter although these abnormalities have also been noted in asymptomatic volunteers [532, 533]. A review on the subject of voiding dysfunction in women included 65 studies with only a small number addressing the diagnostic utility of electromyography [471]. The authors commented that increased EMG activity of the PFM can be seen during voiding or non-relaxation and when this is coupled with pressure-flow information from urodynamics may be useful to differentiate between functional and anatomical obstruction. Further evidence for this comes from a retrospective study of 157 women with roughly equal numbers of women with functional and anatomical obstruction concluding that a low level of EMG activity is characteristic of anatomical obstruction [517]. Additional neurophysiological tests such as anal sphincter EMG, bulbocavernosus reflex, and pudendal sensory evoked potentials can assess the integrity of the somatic S2, 3, 4 nerve roots; however, their clinical utility in the context of non-neurogenic female BOO needs to be better defined [519]. 4.5.4.7 Cystourethroscopy Cystourethroscopy can be useful to visualise any anatomical/mechanical obstruction and provide information regarding its nature, location and calibre. Given that pelvic malignancy may cause anatomical BOO, cystourethroscopy is considered an essential part of the diagnostic pathway. Formal urethral calibration may be useful for women with BOO secondary to urethral stricture disease and various different urethral calibre thresholds have been used, from 14Fr to 20Fr [534]. 4.5.4.8 Urodynamics and video-urodynamics Pressure flow studies are the mainstay of BOO diagnosis and the characteristic abnormalities are a combination of low flow and concomitant high detrusor pressure [518]. However, while the general definition of BOO is well-established with some data supporting its clinical validity in male patients [535], the urodynamic definition of female BOO remains a matter of controversy [515]. Several urodynamic criteria have been introduced during the past 20 years but none have been established as a standard due to lack of clinical validation [515, 536]. The Blaivas and Groutz nomogram which plots free Qmax and maximum detrusor pressure (Pdet,max) measured during urodynamic studies is one of the most popular [537] but has been suggested to overestimate obstruction [74]. The addition of fluoroscopic imaging suggested by Nitti and colleagues introduces a video-urodynamic criterion for obstruction and has found popularity [77]. However, both methods lack data supporting their clinical validity, especially regarding their predictive value for therapeutic intervention outcomes [75]. In a large retrospective study of 1,914 patients, 810 of whom were diagnosed with BOO, several urodynamic cut-off values were determined by ROC curve analysis to optimise the diagnostic accuracy of videourodynamic studies [527]: • PdetQmax of 30 cm H2O or greater for differentiating BOO from bladder dysfunction and normal studies (ROC AUC = 0.78); • the Abrams-Griffiths number greater than 30 for differentiating anatomic from functional BOO (ROC AUC = 0.66); • PdetQmax of 30 cm H2O or greater for differentiating dysfunctional voiding from poor relaxation of the external sphincter (ROC AUC = 0.93). Other smaller studies with a similar methodology of utilising ROC curve analysis have concluded that neither pressure flow data only nor clinical symptoms alone may be sufficient for diagnosing obstruction in women [538], therefore independent validation of any suggested thresholds is necessary. More recently, Solomon and Greenwell devised a female BOO nomogram which parallels the ICS nomogram used for male BOO [539]. It allows the calculation of an alternative BOO female index (BOOIf), using a formula closely aligned to its male counterpart: BOOIf = PdetQmax-2.2Qmax. It is interpreted with a different algorithm however: • BOOIf < 0: less than 10% probability of obstruction; • 5 < BOOIf < 18: equivocal, at least 50% likelihood of obstruction; • BOOIf >18: 90% likelihood of obstruction. The Solomon-Greenwell nomogram is the first which has been tested for clinical validity. In a recent series of 21 unselected consecutive women treated for BOO, the authors observed significant improvement of all urodynamic parameters (Qmax, PdetQmax, BOOIf) in female patients who became asymptomatic post-operatively [540].

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An alternative urodynamic parameter of area under the detrusor pressure curve during voiding (corrected for voided volume) has been proposed following a prospective study involving 103 women [541]. The authors concluded that this variable appears to be the most discriminating urodynamic parameter for the diagnosis of female BOO. This suggested diagnostic method has not been independently validated. Voiding cystourethrography alone or in conjunction with concomitant pressure flow studies may be useful in delineating the site of obstruction. Characteristic features include: • radiographic evidence of obstruction between the bladder neck and distal urethra in the presence of a sustained detrusor contraction [77]; • lack of funnelling appearance of the bladder neck/tight bladder neck in primary bladder neck obstruction; • proximal dilatation of the urethra with distal narrowing in women with urethral stricture disease or pelvic floor hypertonicity. 4.5.4.9

Summary of evidence and recommendations for the diagnosis of bladder outlet obstruction

Summary of evidence The evaluation of LUTS by history and examination alone is insufficient to accurately diagnose female BOO. Urine flow studies cannot diagnose BOO in women with high levels of accuracy. Ultrasound scanning is unable to diagnose BOO in women with high levels of accuracy. Electromyography alone is unable to diagnose BOO in women with high levels of accuracy although it may be of use both in combination with pressure flow studies and in the differentiation of anatomical vs. functional obstruction. Urodynamics (often combined with videofluoroscopy) is the standard test for evaluating female BOO. Recommendations Take a full clinical history and perform a thorough clinical examination in women with suspected bladder outlet obstruction (BOO). Do not rely on measurements from urine flow studies alone to diagnose female BOO. Perform cystourethroscopy in women with suspected anatomical BOO. Perform urodynamic evaluation in women with suspected BOO.

LE 3 3 2b 3

3

Strength rating Strong Strong Strong Strong

4.5.5 Disease management Therapeutic interventions for BOO aim to decrease outlet resistance in order to increase urinary flow, improve bladder emptying and thus reduce voiding and storage LUT symptoms [75, 515, 536]. Treatment choice is commonly dictated by the nature of the underlying cause of the obstruction. 4.5.5.1 Conservative management 4.5.5.1.1 Behavioural modification Behavioural modification aims to improve or correct maladaptive voiding patterns through the analysis and alteration of the relationship between the patient’s symptoms and her environment, lifestyle and habits. Behavioural modification interventions are often tailored to individual patients’ needs, symptoms and circumstances and can include elements such as education regarding normal voiding function, self-monitoring of symptoms, changes in lifestyle factors that may affect symptoms, avoidance of constipation and alteration of voiding technique. Ultimately, techniques aim to improve the coordination between the detrusor and the sphincter resulting in their synergistic action [75, 515, 536]. The vast majority of individual components of self-management have not been critically evaluated and most recommendations are traditionally derived from consensus methodology. General interventions such as those listed above may help with symptoms resulting from BOO but no quantification of their effect is possible. 4.5.5.1.2 Pelvic floor muscle training +/- biofeedback Pelvic floor muscle training aims to improve pelvic floor function and urethral stability. In the context of BOO, physiotherapy aims to teach patients to relax their PFMs and striated urethral sphincter during voiding. Pelvic floor muscle contraction, particularly in women with pelvic floor dysfunction, has been shown to result in a significant reduction in vaginal resting pressure and surface EMG activity [490]. A 12-week PFMT program in post-menopausal women demonstrated significant improvement in the speed of relaxation after PFM contraction and a decrease in the PFM tone [491].

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As mentioned in the section discussing UAB (see Section 4.4.4.1.2 - PFM relaxation training with biofeedback), most of the evidence supporting PFMT in dysfunctional voiding are from studies involving children. A case-series reported improved PFM relaxation and voiding function following PFMT with biofeedback in 15 women with dysfunctional voiding based on a dilated proximal urethra on voiding cystourethrography (VCUG) and hyperactivity of the pelvic muscles or external urethral sphincter on EMG during voiding. No clinical outcomes were reported by this series [542]. 4.5.5.1.3 Electrical stimulation Application of electrodes that allow for controlled contraction and relaxation of the PFM may theoretically facilitate the relaxation of the external sphincter and pelvic floor but no critical evaluation of this intervention in women with BOO has ever been published. 4.5.5.1.4 Use of vaginal pessary Intravaginal devices such as pessaries aim to relieve voiding symptoms and improve bladder emptying by the physical correction of the obstruction caused by a prolapsed pelvic organ. In a prospective study of 18 women with grade 3 to 4 cystoceles and diagnosed with BOO by urodynamics (defined as PdetQmax > 25 cm H20, Qmax < 15 mL/sec), normal voiding was noted in 17 (94%) immediately after placement of a vaginal pessary. No other outcomes were available in this series [543]. No long-term data are available on the use of vaginal pessary for BOO. 4.5.5.1.5 Urinary containment devices Urinary containment devices include body-worn absorbent products. Their use in BOO is to achieve social continence in patients with urinary retention and associated overflow UI and they are often only a temporary measure. There are no published studies on the outcomes or adverse events associated with the use of urinary containment devices for the management of female BOO. While there may be no studies exclusively involving women with BOO, there are many involving women with UI who may have BOO as an underlying cause. 4.5.5.1.6 Urinary catheterisation Significant urinary retention from BOO may be addressed by actively bypassing the obstruction and draining the residual urine. Catheterisation may be used as a treatment itself or as an adjunct to an initial treatment of urethral dilatation or urethrotomy or bladder neck incision. There are two ways of using a catheter: CISC or indwelling catheterisation [115]. Post-UI surgery BOO may be managed by short-term catheterisation for the majority of those who will suffer from transient post-operative voiding difficulty. For a few women who develop chronic urinary retention, CISC or indwelling catheterisation may be offered [471]. A small RCT investigated the effectiveness of CISC to prevent recurrence after internal optical urethrotomy for urethral stricture disease. In the treatment group, CISC was done twice a day for one week, and once a day for 4 weeks, then once weekly for 7 weeks post-urethrotomy. Freedom from stricture recurrence, determined by a urethrogram and uroflowmetry performed 12 weeks post-surgery, was higher in the catheterisation group compared to no catheterisation (78.5% vs. 55.4%) [544]. This finding mirrors the Cochrane systematic review on self-dilatation for urethral stricture among men that showed less recurrence with the performance of selfdilatation [545]. In a series of 20 patients with voiding dysfunction after TVT who were put on a CISC programme, overall cure rate was 59%, with cure defined as consistent residual volume of less than 100 mL. Half of these patients were voiding normally within 12 weeks [546]. A patient satisfaction survey involving 188 patients on CISC/self-dilatation, which included 38 patients with urethral stricture, showed positive (pleased or satisfied) outcomes in 54.3% of all patients, while 28.2% had mixed feelings and 9.6% were unhappy. No rates were given specifically for the BOO group [547]. 4.5.5.1.7 Intra-urethral inserts An intra-urethral insert is a short silicone catheter containing an internal valve and pump mechanism positioned in the female urethra. The valve-pump mechanism is operated by an external control unit, which activates to open the valve and the pump to draw urine from the bladder and allow voiding. At the end of urination the pump ceases to rotate and the valve closes to regain continence. The insert is routinely replaced once a month.

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Only one study reported the use of this device in 92 women with voiding dysfunction of various aetiologies including multiple sclerosis, prior pelvic surgery, pelvic radiation, diabetes mellitus, spinal stenosis and injury. The device was removed within 7 days of insertion in 60% of the cases due to discomfort, pericatheter leakage and technical difficulty. An additional 20% of patients had late discontinuations. All those who continued to use the device were satisfied, with PVR volumes remaining at less than 100 mL. Adverse events included migration into the bladder in 6 cases and symptomatic UTI in 4 cases [548, 549]. Extended, long-term data on the use of urethral inserts are not available. 4.5.5.1.8 Extracorporeal magnetic stimulation Extracorporeal magnetic stimulation involves the patient sitting on a device that induces consistent contraction and relaxation of PFM by repeated magnetic stimulation of motor nerve fibres. Extracorporeal magnetic stimulation contracts and then relaxes the PFM following a set frequency and interval. It is postulated that patients could therefore learn to spontaneously contract or relax the PFM which may enhance their ability to relax their pelvic floor while voiding [550]. In a small (n = 60) prospective non-randomised trial, alfuzosin was compared to EMS and to the combination of alfuzosin + EMS in women with functional BOO. They observed significant increase of Qmax and significant decrease of IPSS in all groups and significantly greater improvement in the QoL question of the IPSS in the combination therapy group [550]. 4.5.5.1.9 S  ummary of evidence and recommendations for conservative treatment of bladder outlet obstruction Summary of evidence Pelvic floor muscle relaxation training with biofeedback may result in relaxation of the pelvic muscles and external urethra in women with dysfunctional voiding. There is no available evidence in the published literature on the clinical effect of ES for the management of female BOO. In women with large (grade 3 to 4) cystoceles causing BOO, placement of a vaginal pessary may improve voiding efficiency. Regular CISC after urethrotomy is better than no catheterisation to prevent recurrence of urethral strictures. A CISC program in women with voiding dysfunction after TVT has a cure rate of 59%. Women who use the intra-urethral device had lower PVR volume but the majority required its removal due to complications. Extracorporeal magnetic stimulation combined with alfuzosin may be more effective than either of these therapies used alone in female patients with functional BOO. Recommendations Offer pelvic floor muscle training (PFMT) aimed at pelvic floor muscle relaxation to women with functional bladder outlet obstruction (BOO). Prioritise research that will investigate and advance the understanding of the mechanisms and impact of PFMT on the coordinated relaxation of the pelvic floor during voiding. Offer the use of a vaginal pessary to women with grade 3 to 4 cystocoeles and BOO who are not eligible/inclined towards other treatment options. Offer urinary containment devices to women with BOO to address urinary leakage as a result of BOO, but not as a treatment to correct the condition. Offer clean intermittent self-catheterisation to women with urethral strictures or post-urinary incontinence surgery for BOO. Do not offer an intraurethral device to women with BOO.

LE 3 NA 3 1b 3 3 2a

Strength rating Weak Strong Weak Weak Weak Strong

4.5.6 Pharmacologic management 4.5.6.1 Alpha-adrenergic blockers Alpha-adrenergic blockers are postulated to relieve LUTS caused by BOO in females via smooth muscle relaxation in the bladder neck thus decreasing bladder outlet resistance [551]. Systematic reviews on the use of alpha-blockers in women generally involve studies with a population that includes females complaining of LUTS and voiding dysfunction. Confirmation of BOO is often not required

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in the trials included in these systematic reviews [552, 553]. These reviews showed significant improvements in symptoms and urodynamic parameters associated with their use [552-554]. A meta-analysis of 14 RCTs comparing alpha-blockers and placebo in women with LUTS showed statistically significant symptom relief after alpha-blocker treatment relative to placebo (MD: -1.60, p = 0.004), but no significant difference in Qmax, PVR and adverse event rates [552]. This is in contrast with prospective non-comparative trials which consistently show improvements in voiding and storage symptoms, bother scores, and urodynamic parameters (Qmax, PVR, PdetQmax, MUCP) after alpha-blocker use compared to baseline [496, 497, 555-557]. A systematic review performed by the Panel of studies on alpha-blocker used specifically for women with BOO included one placebo-controlled RCT, one RCT comparing two types of alpha-blockers, and 6 prospective non-comparative studies. In the only placebo-controlled RCT reporting subgroup analyses in women with urodynamically proven BOO (based on the Bladder and Groutz nomogram) no statistically significant difference was observed in the changes of IPSS, IPSS sub scores, Qmax, PVR and bladder diary after eight weeks of alfuzosin (n = 58) vs. placebo (n = 59). Of note, no EMG and/or voiding cystourethrography was used to distinguish between dysfunctional voiding and primary bladder neck obstruction [558]. Information on the comparative effectiveness of the different types of alpha-blockers is limited to one RCT. A small trial on 37 women with IPSS > 8, Qmax < 12 mL/sec and PVR > 50 mL, compared tamsulosin and prazosin over a 3-month treatment period. More patients on tamsulosin were completely satisfied with their treatment (16/20 vs. 9/20, p < 0.05). Both treatment groups showed significant improvement in symptom scores from baseline but no further statistical comparison between the groups was done. However, a larger decrease in AUA symptom score was seen with the tamsulosin group compared to the prazosin group. More adverse events were reported with prazosin group (13 cases vs. 1 case) [559]. A small three-arm non-RCT in women with functional BOO compared alfuzosin monotherapy and EMS. The combination of alfuzosin and EMS showed greater improvement in storage symptoms and QoL with EMS with or without alfuzosin than with alfuzosin monotherapy alone [550]. 4.5.6.2 Striated muscle relaxants Baclofen is a gamma-aminobutyric acid (GABA) agonist that exerts its effect on the GABAergic interneurons in the sacral intermediolateral cell column responsible for the relaxation of the striated urinary sphincter during voiding. Intrathecal administration has been shown to improve voiding in a trial among spinal cord injured patients. Oral baclofen has also been widely studied [536]. A randomised placebo-controlled crossover trial investigated the efficacy and safety of a 4-week course of oral baclofen 10 mg 3 times/day in 60 women diagnosed with BOO, based on an increased EMG activity with a sustained detrusor contraction during voiding. It showed lower number of voids, significant improvements in Qmax and PdetQmax with baclofen compared with placebo. Post-void residual, maximum cystometric capacity (MCC) and MUCP parameters were not significantly different between groups. Adverse event rates were also similar, with the most common complaints including somnolence, dizziness and nausea. An important limitation of this study was the lack of patient-reported outcomes to assess symptoms and QoL [560]. A small case series reported the outcomes of 20 women with functional BOO who were given oral baclofen 5 mg 3 times/day for 12 weeks. There was significant improvement in the mean voided volume and BVE of the patients. However, Qmax, PdetQmax, PVR and urethral profile pressures did not significantly change. No significant adverse events were noted [561]. 4.5.6.3 Oestrogens The relative reduction in urethral wall compliance seen in atrophic urethritis due to oestrogen deprivation may be responsible for the obstruction in the urethra in post-menopausal women. Oestrogen therapy is thus theoretically expected to improve the condition. There are no published studies on the use of oestrogens specifically for the management of female BOO. 4.5.6.4 Sildenafil Sildenafil, by inhibiting PDE5, increases the levels of nitric oxide in the female urethral sphincter, thereby promoting urethral relaxation. A placebo-controlled randomised crossover trial which included 20 females with partial or complete retention or obstructive voiding, with high MUCP and elevated US-estimated sphincter volume (> 1.6 cm) showed that

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while there was a significant improvement in symptom scores and urodynamic parameters from baseline with sildenafil treatment, this difference was not significant when compared with placebo [562]. 4.5.6.5 Thyrotropin-releasing hormone Intravenous thyrotropin-releasing hormone has been postulated as a neurotransmitter that induces urethral relaxation [563]. The exact mechanism is unclear. In a small RCT of 16 women with voiding difficulty, 8 women (3 with BOO) were randomised to receive 200 ug intravenous bolus of TRH, and 8 (3 with BOO) received saline. No difference in the decline in functional profile lengths and maximum urethral closure pressures were noted between treatment groups, despite a significant decline noted from baseline in the treatment group. No subgroup analysis of women with BOO was reported [563]. 4.5.6.6

Summary of evidence and recommendations for pharmacologic treatment

Summary of evidence Alpha-blocker use is associated with significant improvement in symptom scores from baseline, but not urodynamic parameters compared with placebo. Tamsulosin is associated with greater improvement in symptoms score compared with prazosin. Non-specific alpha-blockers are associated with higher rates of adverse events. Oral baclofen is better than placebo in improving Qmax and PdetQmax, but not other urodynamic parameters. Its effects on symptoms are not well reported. Current evidence does not show that sildenafil is superior to placebo in improving symptoms or urodynamic parameters of female patients with BOO. Trials including women with voiding problems of mixed aetiologies showed no difference in urodynamic outcomes between intravenous thyrotropin-releasing hormone and placebo. Recommendations Offer uroselective alpha-blockers, as an off-label option, to women with functional bladder outlet obstruction (BOO) following discussion of the potential benefits and adverse events. Offer oral baclofen to women with BOO particularly those with increased electromyography activity and a sustained detrusor contraction during voiding. Only offer sildenafil to women with BOO as part of a well-regulated clinical trial. Do not offer thyrotropin-releasing hormone to women with BOO.

LE 1a 1b 1b 1b 1b 1b

Strength rating Weak Weak Strong Strong

4.5.7 Surgical treatment 4.5.7.1 Intra-sphincteric botulinum toxin injection Botulinum toxin inhibits the presynaptic release of acetylcholine, which results in the reduction of the urethral sphincter tone. It is also believed to cause a decrease in the release of norepinephrine in the urethra to counteract external urethral sphincter overactivity [564]. Evidence on the use of botulinum toxin for female BOO is limited to small case series. Most studies included mixed populations without subgroup analyses, or the diagnosis of voiding dysfunction could not be ascertained as solely resulting from BOO. No comparative trial exclusively involving female BOO patients using botulinum toxin has been identified in the literature. A systematic review including several reports of small case series using variable doses of botulinum toxin A injected peri-urethrally in females with dysfunctional voiding showed improvements in symptoms, reduction in residual volumes and reduction in voiding detrusor pressures. Larger series in adults (both males and females, n > 100) showed success rates of 86–100% [564]. In a randomised, double-blind, placebo-controlled study (n = 73) 100 U onabotulinumtoxinA vs. saline resulted in significantly lower IPSS scores and larger voided volumes compared with placebo in 31 adults (men and women with voiding dysfunction [defined by a spinning top appearance on real-time fluoroscopy, poorly relaxed urethral sphincter on EMG, and a normal-to-high voiding pressure with a low and/or intermittent urinary flow rate, a PVR volume > 300 mL, and a low voiding efficiency]). Other urodynamic parameters were comparable between the groups [565]. A subgroup analysis on the female population of this study was not available.

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Two small case series on women with BOO reported the effects of 100 U intra-sphincteric injection of BTA. Both showed improvement in symptom and bother scores and significant reduction in PVR [519, 566]. One study reported increased Qmax and improved static urethral pressure profile (UPP) [519]. The average symptomfree duration was noted to be 16.8 weeks in another study [566]. Adverse events included UTI and temporary need for CISC. No SUI was reported. 4.5.7.2 Sacral nerve stimulation Sacral nerve stimulation is a type of neuromodulation that allows continuous ES from an electrode placed alongside a sacral nerve via a surgically implanted pulse generator. The ES is postulated to decrease the urethral tone. In addition, SNS is also postulated to work by blockage of the inhibitory urethral afferent impulses, which cause inhibition of normal bladder contraction. No comparative trial has been identified in the literature on the use of neuromodulation for female BOO. The majority of the publications on neuromodulation for voiding dysfunction are retrospective reviews of cases, involving a mix of patient populations who underwent the procedure for different indications. In studies that indicated a subgroup of patients with urinary retention, there was either no urodynamic confirmation of the nature of the retention or separate outcomes were not reported for participants with retention. A review of 60 women who underwent sacral nerve stimulation for urinary retention associated with outlet obstruction (defined as UPP > 100 cm H2O, increased urethral sphincter volume > 1.8 mL, and abnormal EMG with repetitive discharges and decelerating bursts) showed an overall spontaneous voiding rate of 72% over a mean follow up of 4 years. Of those who continued to require CISC up to twice/day post-operatively, the frequency was less than prior to surgery (degree not specified). There were 99 adverse events and 63 surgical revisions. In this series, half of the patients underwent a one-stage SNS procedure and the other half a twostage procedure. The proportion of patients who required CISC-assisted voiding was higher in the two-stage group (27% vs. 17%). More serious adverse events (defined as ‘events requiring admission or surgical revision to resolve issues such as loss of response, lead migration and surgical revisions’) were associated with the one-stage procedure [562]. A single-centre series in a subgroup of 32 patients diagnosed with idiopathic urinary retention (Fowler’s syndrome) who underwent SNS, 62.5% achieved a > 50% reduction in the CISC rate [567]. 4.5.7.3 Pelvic organ prolapse surgery Pelvic organ prolapse surgery may relieve BOO by correcting the urethral kinking caused by the prolapse or by relieving the urethral compression brought about by the prolapsing organ [75, 515, 536]. No comparative studies on prolapse surgery for female BOO have been published. Bladder outlet obstruction due to POP may be addressed by corrective surgery. Based on reviews, the majority of patients who had BOO caused by POP who had a repair of their cystocoele demonstrated improvement of their voiding difficulties [471, 568]. A multicentre prospective study involving 277 women with at least grade 2 symptomatic POP who underwent surgery demonstrated a significant reduction in voiding symptoms and PVR volume one year post-operatively [569]. A retrospective study of 50 women who underwent laparoscopic sacrocolpopexy for POP showed a significant increase in the mean post-operative Qmax and a decrease in the PdetQmax and PVR in those ≥ 65 years old. The OAB symptom score (OABSS) improved but there was no significant difference in the ICIQ-SF score postoperatively [570]. In a case series of 35 females with stage 3-4 POP presenting with a pre-operative PVR > 100 mL (mean 226 mL), 89% had PVR volumes of < 100 mL post-surgery [571]. In another case series of 39 patients with cystocoeles who complained of voiding symptoms pre-operatively, 30 (79%) achieved normal voiding, defined as no obstructive symptoms and a PVR below 50 mL, after bladder neck suspension with anterior colporrhaphy [572]. 4.5.7.4 Urethral dilatation Urethral dilation involves the passage of sequentially greater diameter dilators into the urethra, causing the obstructing fibrotic tissue to break open and thereby widening the lumen. It is considered the primary

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procedure of choice for women suspected of urethral stricture disease [534]. Dilation of up to 30-40Fr has been done. There is no standard dilatation technique; dilatation of up to 43F has been described, although other authors suggest dilating to 30Fr or 35Fr. A systematic review on female urethral stricture management included 3 trials involving urethral dilatation. Pooled analysis from these studies with data from 93 females showed a mean success rate of 49% after urethral dilation to 41Fr with a mean follow up of 46 months. Mean time to failure was 12 months. In treatmentnaïve patients, success rate (as defined by trialists) was 58% while in patients who had undergone previous dilatation, success rate was 27.2% [530]. An RCT of 50 women with OAB syndrome and associated urodynamically-confirmed BOO (defined as a Qmax of less than 15 mL/sec with a voided volume of 100 mL or above and/or PVR volume over 200 mL, not due to a urethral stricture) compared the effect of cystoscopy and bladder distension with urethral dilatation (22) and cystoscopy only (28) after 6 week follow-up. Significantly more patients who had cystoscopy only had persistent urgency at 6 weeks and 6 months post-operatively. Urodynamic parameters did not significantly change pre- and post-operatively in both groups. The greater improvement in QoL scores based on the King’s Health Questionnaire (KHQ) domain scores seen in the non-urethral dilatation group in this trial should be interpreted cautiously because of the higher baseline scores in this group. Of note, there were no significant changes in Qmax, PVR, voided volume or PdetQmax in any of the two groups at 6 weeks questioning the role of any of these two options for the therapeutic management of BOO. Also, six patients (12%) developed postoperative SUI [573]. A prospective trial of 86 women with primary urethral stricture compared on-demand vs. intermittent urethral dilatation to 24Fr (dilate every 2 months). It showed an overall increase in Qmax and decrease in PVR postdilatation. Significantly greater improvements were seen in the intermittent urethral dilatation group [574]. Three small case series showed improvements in symptoms with relief of urgency and/or UUI but inconsistent results in terms of significant improvement in Qmax, PVR and PdetQmax. Benefits were poorly sustained, with the majority of patients requiring additional or repeat intervention in the long-term [575-577]. Worsening or new-onset SUI is a concern with urethral dilatation but it is less of a concern than after urethrotomy or surgical reconstruction. Patients have also reported frequency and urgency post-dilatation [577]. 4.5.7.5 Urethrotomy Urethrotomy involves the incision of the urethra endoscopically or using a urethrotome. It addresses the urethral narrowing by cutting open the scar tissue which is causing the obstruction [75, 515, 536]. No comparative study has investigated the effectiveness of urethrotomy in female BOO. A prospective study of 10 females with urethral strictures investigated the effect of Otis urethrotomy to 40Fr followed by 6 weekly dilatations. There was significant improvement in IPSS, QoL, voided volume, Qmax and PVR at 6 months. Only the improvements in PVR and QoL were maintained on long-term follow-up (mean 82 months) [575]. 4.5.7.6 Bladder neck incision/resection Transurethral bladder neck incision decreases the resistance at the bladder neck by cutting open the hypertrophic bladder neck smooth muscle in patients with primary bladder neck obstruction. Transurethral incision of the bladder neck may be performed with a unilateral incision at 12 o’clock or with bilateral incisions placed at the 5 and 7 o’clock or at 2 and 10 o’clock or at 3 and 9 o’clock positions, or 4 incisions at 3, 6, 9 and 12 o’clock. This may be done using a resectoscope with a Collin’s knife, a cold knife, or using laser energy. Some authors report additional resection of the bladder neck between the 5 and 7 o’clock positions during the procedure. Evidence on bladder neck incision or resection for female BOO is limited to non-comparative trials. A review of studies on bladder neck incision for the treatment of bladder neck obstruction in women reports success rates between 76–100% [518]. Bladder neck incision was compared with V-Y-reconstruction using Nesbit’s technique in a retrospective study of 17 females with BOO, diagnosed by various uroradiological, endoscopic and urodynamic investigations. The results showed similar symptomatic improvement rates and post-operative PVRs between the two groups. V-Y plasty was noted to have a longer operative- and catheter time, lower uroradiological improvement rate, higher transfusion rate, and higher adverse event rate [578].

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Several prospective case series consistently reported significant improvements in IPSS, QoL, Qmax, PdetQmax and PVR after treatment compared to baseline, regardless of the site of the incision, type of energy used or the length of follow up [579-582]. The largest case series with 84 patients diagnosed with primary bladder neck obstruction (based on the lack of funnel shape of the bladder neck during voiding on voiding cystourethrogram, a Pdet > 20 cm H20 and a Qmax < 12 mL/sec) showed success in 84.5% of patients with improvement in IPSS, QoL, Qmax and PdetQmax after a mean follow up of 27.4 months (6–78 months). Complications included vesico-vaginal fistula (VVF) (3.6%), SUI (4.7%) and urethral stricture (3.6%) [579]. No comparisons have been made between the different incision techniques (location of incision, length, depth, implement used – cold knife vs. hot knife vs. laser, with or without resection). However, in a case series of 84 patients, complications of VVF and SUI were noted in the cohort of patients who had their incisions at 5 & 7 o’clock, and not in those who had their incisions at 2 & 10 o’clock [579]. Adverse events include SUI, requirement for re-operation and recurrence. Post-operative SUI was reported in 3-33% [518]. 4.5.7.7 Urethroplasty/urethral reconstruction The surgical reconstruction of the female urethra has been used in the management of extensive female urethral stricture. Several urethroplasty techniques have been reported including the use of vaginal or labial flaps, as well as vaginal and buccal grafts after cutting open the fibrotic tissue causing the urethral obstruction [583]. The use of bladder flaps has also been reported [584]. Recently laboratory-engineered tissue grafts have also been used [585]. The surgical approaches have been described based on the position relative to the urethra; dorsal, ventral or circumferential. The dorsal approach is believed to provide better mechanical support and a more vascularised bed for a graft or flap. However, there is greater risk of damage to the sphincter and clitoral bodies with this approach. The ventral approach is more familiar to most surgeons and requires less urethral mobilisation. However, it is reported as being more prone to urethra-vaginal fistulae, although it is not clear to what extent [534]. Reviews of studies reporting outcomes of urethroplasties state success rates ranging from 57–100% [534, 586]. Pooled analysis from 6 studies using vaginal or labial flaps showed a mean success rate of 91% with a mean follow-up of 32 months. Vaginal or labial graft urethroplasty was reported to have an 80% success rate with a mean follow-up of 22 months. Oral mucosal grafts, reported in 7 studies, had a mean success of 94% after a mean 15-month follow up [534]. A later review of studies on dorsal buccal mucosal reported graft success rates of 62-100%, pooled success rate 86% [587]. Stricture recurrence rate in a long-term study with a mean follow-up of 32 months showed a stricture recurrence rate of 23.1% [586]. A retrospective comparative study on 10 females who underwent urethral dilatation and 12 who underwent dorsal onlay pedicled labium flap urethroplasty, reported both groups with significant improvements from baseline in terms of QoL, AUA symptom score, PVR and Qmax. The urethroplasty group had significantly better QoL scores and Qmax (17.0 vs. 12) on follow-up as compared to the dilatation group [588]. Adverse events associated with urethroplasties include new-onset SUI and urgency and worsening of UUI. 4.5.7.8 Urethrolysis Bladder outlet obstruction in females occurring as a complication of surgical procedures for SUI may be managed surgically by lysis of the urethra aiming to regain urethral mobility. Urethrolysis may involve removal of peri-urethral anti-incontinence sutures, scar tissue and fibrosis. No comparative trials have been published on urethrolysis. Case series showed success rates measured as improved voiding and lower residual volumes, improvement or resolution of symptoms and QoL and improvement of urodynamic parameters post treatment [589-591]. De novo SUI was reported in 39% in one study [591]. A study on 21 patients who underwent urethrolysis suggested an association of persistent post-operative bladder symptoms with greater delay in doing urethrolysis. Patients who presented with post-operative storage and voiding symptoms after a mean of 17 months follow-up had a longer time to urethrolysis compared to those who had no complaints (31 vs. 9 months) [592].

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4.5.7.9 Removal/excision/section/loosening of mid-urethral sling In women who develop BOO after placement of a mid-urethral sling, surgical management may include tape loosening, incision or division, and excision and/or removal of the tape [471]. Several small retrospective reviews of cases using different techniques of sling revision (incision, partial excision, excision) showed good success rates in terms of symptom reduction, resumption of voiding with significant reduction in PVRs and improvement of urodynamic parameters. Stress UI recurs in a very small proportion of patients and often to a lesser degree than prior to the sling procedure. Studies show long-term efficacy, including preservation of continence. In a series of 63 females who presented with voiding dysfunction and persistent PVR > 100 mL after tape surgery for UI, different techniques were compared. Comparisons involved sling revision (sling division (n = 46) vs. partial sling excision (n = 13) vs. sling revision (division or excision) with an additional anti-SUI procedure (n = 4). The authors reported an overall success rate of 87% (success defined as PVR < 150 mL). No statistically significant difference in success rates was demonstrated across the different revision techniques. There was a higher need for surgery for recurrent SUI in the partial sling excision group without an anti-SUI procedure (23% vs. 2.2 and 0) [593]. 4.5.7.9.1 Timing of sling revision One study showed that patients who underwent surgical release more than 180 days after initial anti-UI surgery had significantly less recurrent SUI as compared to patients who underwent the release sooner (15% vs. 46%, p = 0.0008) [594]. 4.5.7.10

Summary of evidence and recommendations for surgical management of BOO

Summary of evidence Intrasphincteric injection of botulinum toxin results in the improvement of symptoms and urodynamic parameters. Sacral nerve stimulation results in spontaneous voiding and a reduction in CISC rate in the majority of female BOO patients in idiopathic urinary retention. More serious adverse events and surgical revisions were associated with the one-stage neuromodulator implantation procedure. Repair of pelvic organ prolapse improved PVR volume and voiding symptoms. Urethral dilatation in women with BOO results in significant improvement in OAB symptoms, but improvements in urodynamic parameters of voiding are inconsistent. Programmed intermittent urethral dilatation results in better outcomes compared with on demand dilatation. Effects of urethral dilation are poorly sustained, requiring repeat intervention in the long term. Internal urethrotomy followed by regular dilatations resulted in significant improvement in symptoms and urodynamic parameters in women with BOO. Bladder neck incision in females with BOO results in improvements in symptoms and urodynamic parameters. Complications of bladder neck incision are not common, but include vesico-vaginal fistula, SUI, and urethral stricture. Urethroplasty using grafts or flaps in women with BOO due to urethral stricture have good success rates with significant improvements of symptoms, QoL scores and urodynamic parameters compared to baseline. Urethroplasty results in better QoL and Qmax compared to urethral dilatation. Long-term results showed significant stricture recurrence rate after urethroplasty. Urethrolysis performed on women with voiding problems after anti-UI surgery resulted in improvements in symptoms, QoL and urodynamic parameters post-operatively. Delayed urethrolysis was associated with persistent post-operative bladder symptoms. Sling revision in women who presented with urinary retention or voiding problems and significant PVRs after sling surgery for UI resulted in improvements in symptoms and urodynamic parameters, resumption of voiding and reductions in PVRs. Sling revision is associated with the risk of recurrent SUI.

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2 3 3 3 3

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Recommendations Offer intrasphincteric injection of botulinum toxin to women with functional bladder outlet obstruction (BOO). Offer sacral nerve stimulation to women with functional BOO. Advise women with voiding symptoms associated with pelvic organ prolapse (POP) that symptoms may improve after POP surgery. Offer urethral dilatation to women with urethral stenosis causing BOO, but advise on the likely need for repeated intervention. Offer internal urethrotomy with post-operative urethral self-dilatation to women with BOO due to urethral stricture disease but advise on its limited long-term improvement and the risk of post-operative urinary incontinence (UI). Do not offer urethral dilatation or urethrotomy as a treatment for BOO to women who have previously undergone mid-urethral synthetic tape insertion due to the theoretical risk of causing urethral mesh extrusion. Inform women of limited long-term improvement (only in terms of post-void residual and quality of life) after internal urethrotomy. Offer bladder neck incision to women with BOO secondary to primary bladder neck obstruction. Advise women who will undergo bladder neck incision on the small risk of developing stress urinary incontinence (SUI), vesico-vaginal fistula or urethral stricture post-operatively. Offer urethroplasty to females with BOO due to recurrent urethral stricture after failed primary treatment. Caution women on the possible recurrence of strictures on long-term follow-up after urethroplasty. Offer urethrolysis to women who have voiding difficulties after anti-UI surgery. Offer sling revision (release, incision, partial excision, excision) to women who develop urinary retention or significant voiding difficulty post tape surgery for UI. Caution women about the risk for recurrent SUI and the need for a repeat/concurrent anti-UI surgery after sling revision.

Strength rating Weak Weak Weak Weak Weak

Weak

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4.5.8 Follow up Women with BOO should be followed up and monitored regularly due to the risk of further deterioration of voiding or renal function in case of persistence and progression of the obstruction. For those who received treatment, monitoring must be done for the recurrence of the BOO. In particular, women who underwent urethral dilation, urethrotomy or urethroplasty for urethral stricture need to be monitored for the recurrence of the stricture.

4.6

Nocturia

Nocturia was defined by the ICS in 2002 as ‘the complaint that the individual has to wake at night one or more times to void’ and quantified in an updated document in 2019 as ‘the number of times an individual passes urine during their main sleep period, from the time they have fallen asleep up to the intention to rise from that period’ [595]. A systematic review of the literature in this topic area has been conducted by the EAU Guidelines Panel on Urinary Incontinence covering publications up to and including 2017 [596]. This was supplemented with a scoping search in 2020 covering more recent publications. 4.6.1 Epidemiology, aetiology, pathophysiology The prevalence of nocturia varies according to age with around 4–18% of women aged 20-40 experiencing 2 or more episodes per night, compared to 28–62% of women aged 70 or older [597]. In a study of 1,000 community-dwelling older adults, nocturia in females was associated with older age, African-American race, a history of UI, swelling of the lower limbs and hypertension [598]. A report on over 5,000 adults aged 30–79 years identified around 28% with nocturia and found additional correlates with increased BMI, cardiac disease, type 2 diabetes and diuretic use [599]. A recent systematic review and meta-analysis has concluded that nocturia is probably associated with an approximate 1.3 fold increased risk of death [600]. The aetiology of nocturia is multifactorial and can include both urological and non-urological causes. Urological conditions which may exhibit nocturia as a significant symptom include OAB syndrome, BOO, DU and dysfunctional voiding. Non-urological causes include 24 hour polyuria (which includes nocturnal polyuria), congestive heart failure, sleep apnoea, restless leg syndrome, peripheral vascular disease, sleep disorders, night-time food ingestion, dependent oedema and excessive fluid intake [601]. Given the varied aetiology of

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this symptom there are a range of possible pathophysiological mechanisms. These include: (1) 24 hour polyuria (e.g. diabetes mellitus, primary polydipsia, and diabetes insipidus); (2) nocturnal polyuria (e.g. behavioural, peripheral oedema, obstructive sleep apnoea, glycosuria, hormonal abnormalities and cardiac dysfunction); (3) diminished bladder capacity (e.g. OAB syndrome/DO, pelvic floor dysfunction, BOO, pharmaceuticals, LUT calculi or tumours and neurological bladder dysfunction); and (4) primary or secondary sleep disorders [602]. 4.6.2 Classification Classification of nocturia is dependent on bladder diary analysis and several parameters have been defined as important [603]: • Nocturnal urine volume - total volume of urine passed during the night (this includes the 1st morning void but does not include the last void prior to sleep); • Maximum voided volume - the largest single voided volume in 24 hours; • Nocturia index - the nocturnal urine volume divided by the maximum voided volume; • Nocturnal polyuria index - the nocturnal urine volume divided by the 24 hour urine volume; • Nocturnal urine production - the nocturnal urine volume divided by the duration of sleep in hours. The analysis of these parameters will allow the clinical classification of nocturia based on the physiological abnormalities that can cause nocturia: • 24 hour polyuria; • nocturnal polyuria; • diminished bladder capacity; • sleep disorders. 4.6.3 Diagnostic evaluation The evaluation of nocturia should include a thorough medical history and physical examination with particular reference made to a history of sleep disorders, fluid balance, associated LUTS, cardiovascular and endocrine comorbidities, renal disease, current medications and previous urological history [603]. Several nocturia-specific symptom scores exist such as the ICI Questionnaire-nocturia, the Nocturia Quality of Life Questionnaire (N-QoL) and the Nocturia Impact Diary, some of which were developed in men. A further screening tool is also available which aims to identify causes of nocturia; the Targeting the individual’s Aetiology of Nocturia to Guide Outcomes (TANGO) assessment tool [604-606]. A bladder diary is a vital initial investigation in any patient that is complaining of nocturia and further supplementary investigations are guided by any abnormalities identified. Bladder diary analysis can allow for the calculations of the parameters detailed in Section 4.6.2. A low nocturnal bladder capacity or global bladder capacity will be highlighted by reduced voided volumes either during nocturnal hours or both night and day. This may suggest an underlying urological condition such as OAB syndrome, BOO or DU. Global polyuria is defined as a 24-hour urine production of more than 40 mL/kg [607] and may be present in conditions such as diabetes mellitus or diabetes insipidus. The definition of nocturnal polyuria is age dependent and the thresholds for this diagnosis range from 20% (in younger persons) to 33% (in those over 65) of the 24 hour urine volume being produced during sleeping hours. This may also be observed in patients with loss of circadian rhythm, cardiovascular disease, sleep apnoea or sleep disorders [603]. A large study conducted across European and American centres involving almost 2,000 patients has identified nocturnal polyuria as a contributory cause of nocturia in 89% of patients who were being treated for LUT abnormalities such as OAB syndrome or benign prostatic enlargement [608]. As an alternative to a three, or more, day bladder diary a nocturnal-only diary has been investigated in men [609]. Overall, results showed acceptable sensitivity and specificity from the nocturnal bladder diary in comparison with the standard bladder diary for the majority of parameters. The nocturnal-only diary was obviously not able to diagnose 24 hour polyuria and has not yet been validated for use in women. 4.6.3.1

Summary of evidence and recommendations for the diagnosis of nocturia

Summary of evidence A thorough medical history is an integral part of the evaluation of women presenting with nocturia. Nocturia-specific questionnaires are sensitive to symptom changes. A bladder diary allows for calculation of important indices and can identify potential causes of nocturia. Nocturnal-only bladder diaries have been evaluated in men only.

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Recommendations Take a complete medical history from women with nocturia. Use a validated questionnaire during the assessment of women with nocturia and for re-evaluation during and/or after treatment. Use a three-day bladder diary to assess nocturia in women. Do not use nocturnal-only bladder diaries to evaluate nocturia in women.

Strength rating Strong Weak Strong Weak

4.6.4 Disease management When evaluating the results of trials involving treatment strategies for nocturia it is vital to examine for clinical significance as statistical significance can be achieved with very small reductions in nocturia episodes. 4.6.4.1 Conservative management The individual components of self-management have not been critically evaluated and most recommendations are traditionally derived from consensus methodology. Interventions such as those listed below may help with nocturia but, for the majority, no quantification of their effect is possible: • reduction of fluid intake at specific times; • avoidance/moderation of intake of caffeine or alcohol; • distraction techniques; • bladder retraining; • PFMT; • reviewing medication; • treatment of constipation. The available data for conservative treatment of nocturia exhibit significant heterogeneity. In the EAU systematic review [596], three studies [610-612] were favourable for conservative treatment with PFMT, with another failing to confirm benefit [613]. The highest level of evidence comes from a study of 131 patients (as a secondary analysis from a prospective RCT which had urgency-predominant UI as the primary inclusion criterion) and found that training in PFM contraction, which included 4 sessions of biofeedback-assisted PFMT reduced nocturia by a median 0.50 episodes per night and was significantly more effective than anticholinergic drug treatment or placebo [610]. The certainty of evidence associated with this treatment is moderate. A smaller RCT of 50 women with “urinary complaints”, randomised 1:1 to bladder training and PFMT compared to a control group receiving no treatment, showed a significant decrease in patients’ complaints of nocturia [611]. Another RCT in only 24 women compared PFMT only to transcutaneous electrical nerve stimulation therapy (TENS) plus PFMT [612]. Although the authors did not find significant differences between the groups, the change in nocturia episodes before and after treatment was statistically significant in both groups. This study was underpowered by the authors’ own admission. The level of certainty of the evidence from these two trials is low. In a secondary analysis from a prospective RCT, 210 women with UUI were evaluated for change from baseline in the number of episodes of nocturia and nocturnal incontinence between groups allocated to medical treatment (tolterodine ER 4 mg) alone vs. medical treatment plus PFMT [613]. No significant difference between the groups was found and the actual difference in nocturia episodes in either treatment arm was small. The level of certainty of the evidence from this trial is low. A recent RCT has explored both individual and group PFMT with a specific secondary outcome of number of patients with two or more nocturia episodes per night [328]. The authors reported similar reductions with over 30% of patients who had two or more episodes of nocturia at baseline no longer experiencing this level of symptoms at one year following PFMT. One small, single-centre RCT in which functional magnetic stimulation (FMS) was compared to no treatment in 39 women reported a significant decrease in nocturia (together with voiding frequency and pad use) in the treatment group compared to the control group [614]. In patients with obstructive sleep apnoea who complain of nocturia, treatment with continuous positive airway pressure has been shown to be effective in a systematic review and meta-analysis of 5 RCTs involving both male and female patients [615]. This treatment was associated with an average numerical reduction in nocturia of over two episodes per night.

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4.6.4.1.1 Summary of evidence and recommendations for the conservative management of nocturia Summary of evidence Individual or group PFMT appear to be equally effective in terms of reduction in nocturia episodes. The majority of studies evaluating PFMT for nocturia in women with additional urinary symptoms have shown positive results both in comparison to placebo and to anticholinergic drugs. Treatment of nocturia secondary to obstructive sleep apnoea with continuous positive airway pressure results in reductions in nocturia episodes.

Recommendations Offer women with lower urinary tract symptoms (LUTS) lifestyle advice prior to, or concurrent with, treatment. Offer pelvic floor muscle training for nocturia (either individually or in the group setting) to women with urinary incontinence or other storage LUTS. Offer women with nocturia and a history suggestive of obstructive sleep apnoea a referral to a sleep clinic for an assessment of suitability for continuous positive airway pressure treatment.

LE 1b 1b 1a

Strength rating Strong Strong Strong

4.6.4.2 Pharmacology management 4.6.4.2.1 Desmopressin Desmopressin is a synthetic analogue of the hormone vasopressin and is most often used for management of nocturia due to nocturnal polyuria. In the recent systematic review [596] 3 trials specifically conducted in women were found but more additional data could be extracted from studies in mixed populations. The earliest evidence comes from a 1982 single-site crossover trial involving 25 women treated with either 20 mcg of desmopressin or placebo revealed a significant decrease in nocturnal urine output at 6 weeks [616]. A more recent multicentre, multinational double-blind RCT involving 141 women used desmopressin in doses 0.1, 0.2, 0.4 mg orally at bedtime after a dose-titration period [617]. This increases the likelihood of a positive outcome because non-responders were excluded at this stage. At 3 weeks significant reductions in nocturnal urinary frequency and nocturnal diuresis were reported. In another multicentre double-blind RCT a total of 58 women were randomised into 5 groups (12 receiving placebo, 12 receiving desmopressin 10 μg, 11 receiving 25 μg, 11 receiving 50 μg and 12 receiving 100 μg) for 4 weeks [618]. A dose-response relationship was observed and female patients appeared more sensitive to desmopressin. Statistically significant changes in nocturnal urine volumes were reported in favour of the higher desmopressin dose. Differences in the nocturnal polyuria index also tended to favour desmopressin over placebo and favoured the higher desmopressin dose. The level of certainty of the evidence from these 3 trials is low. Desmopressin can be safely combined with anticholinergics with significant benefit in women with OAB and nocturnal polyuria, as shown by a multicentre RCT of 97 patients [619]. A post-hoc analysis of data comparing 3-month once-daily combination (desmopressin 25 μg/tolterodine 4 mg, n = 49) or monotherapy (tolterodine 4 mg/placebo, n = 57) revealed a significant reduction in nocturnal void volume and time to first nocturnal void in favour of combination therapy. The level of certainty of the evidence from this trial is moderate. Pooled data from three RCTs were used to examine the adverse event profile of desmopressin, specifically hyponatraemia [620]. The authors reported that the majority tolerate desmopressin treatment without clinically significant hyponatremia, but risk increased with age and lower baseline serum sodium concentration. They advised that desmopressin treatment in elderly patients should include careful monitoring of the serum sodium concentration and should be avoided in patients with a baseline serum sodium concentration below normal range [620]. 4.6.4.2.2 Anticholinergics The systematic review [596] identified 3 RCTs involving anticholinergics such as oxybutynin 2.5 mg/day [610] and tolterodine 4 mg/day [613, 619]. A secondary analysis from a prospective RCT involving 131 women with nocturia followed up for 8 weeks found that women receiving 2.5 mg once a day immediate-release oxybutynin (with the possibility of self-titration and dose escalation to 5 mg three times a day) had less nocturia episodes than women receiving placebo [610]. Women receiving oxybutynin plus behavioural therapy also exhibited a statistically significant decrease in nocturia episodes compared to both placebo and oxybutynin alone. A multicentre RCT which included 305 women followed up for 8 weeks examined the efficacy of tolterodine tartrate 4 mg alone or in combination with behavioural training [613]. Statistically significant differences

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compared to baseline were observed in mean nocturia episodes and nocturnal incontinence episodes in both groups, but no difference was reported between the two treatment groups. The level of certainty of the evidence from this trial is moderate. In an RCT including 97 women with nocturnal polyuria and OAB syndrome, comparing three months of oncedaily combination (desmopressin 25 μg/tolterodine 4 mg, n = 49) or monotherapy (tolterodine 4 mg/placebo, n = 57) a significant reduction in mean number of nocturnal voids compared to baseline was reported in both groups [619]. The level of certainty of the evidence from this trial is moderate. A well-designed large comparative study followed 407 women with OAB and nocturia for 4 weeks [621]. The patients were given tolterodine as monotherapy in one group, and tolterodine combined with estazolam (a benzodiazepine) in the other group for four weeks. Significant changes from baseline in both groups for the main outcome of number of nocturia episodes were reported. The combination showed a significant benefit for women with OAB and nocturia compared to monotherapy in terms of differences in number of nocturia episodes per night, urgency episodes in 24 hours, UUI episodes in 24 hours, voided volume per micturition. The level of certainty of the evidence from this trial is very low. 4.6.4.2.3 Oestrogens In the recent systematic review [596] only a single RCT investigating the efficacy of oestrogen for nocturia was identified [622]. This trial compared an oestradiol-releasing vaginal ring with an oestriol vaginal pessary in 251 women followed up for 6 months. There was no difference between the treatment groups in the number of women reporting nocturia though they reported significant change from baseline in both treatment arms with over 50% of subjects responding in each arm. The certainty of evidence for this outcome was low. 4.6.4.2.4 Diuretic treatment In a randomised placebo-controlled study an afternoon dose of 40 mg of furosemide (taken 6 hours before bedtime) in an attempt to establish and complete a diuresis before bedtime was given to elderly men [623]. In the 43 men who completed the study, night-time frequency in the furosemide group fell by 0.5 compared to placebo, and percentage night-time voided volume fell by 18%. No such study has been carried out in female patients. 4.6.4.3 Surgical management Surgical treatment is in general reserved for those with underlying correctable LUT disorders. The effect of surgical treatments on symptom of nocturia can be found in the relevant condition-specific sections of this guideline. 4.6.4.4

Summary of evidence and recommendations for the pharmacological management of nocturia

Summary of evidence Desmopressin treatment for nocturia shows significant reductions in nocturnal urine output, nocturnal urinary frequency and nocturnal polyuria index. The majority of nocturia patients tolerate desmopressin treatment without clinically significant hyponatremia; however, the risk increases with increasing age and decreasing baseline serum sodium concentration. Treatment of nocturia in OAB patients with anticholinergic drugs shows reduction in nocturia episodes. Combination of PFMT and pharmacological treatment with anticholinergics does not appear to confer additional benefit over anticholinergics alone. Combination of anticholinergic and desmopressin treatment appears to reduce nocturnal voided volume and time to 1st nocturnal void in women with nocturnal polyuria. Vaginal oestrogen may be beneficial in the treatment of nocturia in around 50% of women. Afternoon (timed) diuretic treatment with furosemide reduces nocturia episodes and nocturnal voided volume in men but no similar studies have been conducted in women. Examination for clinical significance is important when evaluating the results of trials involving treatment strategies for nocturia as statistical significance can be achieved with very small reductions in nocturia episodes.

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Recommendations Offer desmopressin treatment for nocturia secondary to nocturnal polyuria to women following appropriate counselling regarding the potential benefits and associated risks (including hyponatremia). Carefully monitor serum sodium concentration in elderly patients treated with desmopressin. Avoid prescribing desmopressin to patients with a baseline serum sodium concentration below normal range. Offer a anticholinergic treatment for nocturia to women with urgency incontinence or other storage lower urinary tract symptoms following appropriate counselling regarding the potential benefits and associated risks. Inform women with nocturia that the combination treatment with behavioural therapy and anticholinergic drugs is unlikely to provide increased efficacy compared with either modality alone. Offer combination treatment with anticholinergics and desmopressin to women with OAB and nocturia secondary to nocturnal polyuria following appropriate counselling regarding the potential benefits and associated risks. Offer vaginal oestrogen treatment to women with nocturia following appropriate counselling regarding the potential benefits and associated risks. Offer timed diuretic treatment to women with nocturia secondary to polyuria following appropriate counselling regarding the potential benefits and associated risks.

Strength rating Strong

Strong

Strong

Weak

Weak

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4.6.5 Follow-up The follow-up of patients with nocturia will be dependent on both the underlying aetiology of this symptom and the treatment given.

4.7

Pelvic organ prolapse and LUTS

4.7.1 Epidemiology, aetiology, pathophysiology Pelvic organ prolapse is a common condition in adult women. The prevalence of POP ranges from 3-6% when bothersome symptoms are used to characterise the condition and goes up to as high as 50% when a purely anatomical definition is used [624]. The lifetime risk for POP surgery is an estimated 12.6% [625]. Parity, vaginal delivery, ageing and obesity are the most commonly recognised risk factors [626]. Although the aetiology of POP is not fully understood, birth trauma to the levator ani complex is recognised as central to its development. In normal physiology an intact levator ani complex functionally closes the genital hiatus surrounding the vagina limiting the pressure gradient between the intra-abdominal and intravaginal areas. During physical activities this reduces the stress on the endopelvic fascia and its condensations (e.g. ligaments), which are crucial in securing the bladder, uterus and rectum to their surroundings. Current aetiological concepts include widening of the levator hiatus due to birth trauma, which will create a lowpressure area in the vagina and consequently an increased stress on the ligaments, fascial elements and PFMs during physical activity. When the supporting function of the muscles and connective tissues fail, POP may develop [627]. This concept also explains the time lapse between birth trauma and the occurrence of POP. Pelvic organ prolapse and LUTS often occur simultaneously in women. Although in isolation both POP and LUTS are already prevalent conditions in women, the prevalence of LUTS in women with POP exceeds that of LUTS in women without POP symptoms [624]. The observation that LUTS symptoms may improve, or worsen, after POP treatment also suggests a link between these two entities [624]. Clinical examples include the occurrence of BOO symptoms in the case of a severe POP, and the disappearance of SUI symptoms with progression of POP (and conversely the occurrence of SUI after treatment of POP) [628]. 4.7.2 Classification Since 1996 POP has been classified according to the Pelvic Organ Prolapse-Quantification (POP-Q) system [629]. For specifics on how to perform the POP-Q measurement and the 9 standard points to be measured, as shown in Figures 2 and 3, we refer to the original publications [629, 630]. The vagina is divided into anterior (bladder), posterior (rectum) and apical (cervix or vaginal vault) compartments. After scoring the position of the 9 POP-Q points, a prolapse of each compartment is graded numerically from stage 0 to 4, with stage 0 being no prolapse and stage 4 being a complete eversion of the uterus/vaginal vault. A crucial landmark in staging of the POP is the hymenal remnant. Any POP with

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a maximum descent that is still 1 cm above the hymen (e.g. in the vagina) is considered a stage 1 POP. A maximum descent between 1 cm above and 1 cm below (outside the vagina) the hymen is a stage 2 POP. Any descent beyond 1 cm below the hymen is a stage 3 POP. The figures below show the POP-Q staging in comparison to the Baden Walker system (and others) used before the international consensus on the POP-Q staging was introduced as the new standard. Figure 2: Prolapse classification system*

*Figure reproduced with permission from the publisher, from Theofratus JP, et al. [630]. Figure: 3: Pelvic Organ Prolapse-Quantification staging*

*Figure reproduced with permission from the publisher, from Bump RC, et al, [629]. The standardisation of terminology of female pelvic organ prolapse and pelvic floor dysfunction. 4.7.3 Diagnostic evaluation Pelvic organ prolapse is a clinical diagnosis and is staged according to the POP-Q system. In general, a POP that is above the hymen should only produce mild symptoms at most [631]. In cases where there is a discrepancy between the clinical symptoms and POP-Q staging, it is advised to consider performing the POP-Q measurement in a standing position rather than supine, or re-evaluate at a later time in the day. Magnetic resonance imaging assessment demonstrated a marked difference in POP staging between supine and standing position [632]. Additional diagnostic tests for POP are mainly indicated if there are accompanying symptoms like LUTS or bowel dysfunction. Imaging techniques are not advised for the routine diagnostic workup of patients presenting with POP [67]. The role of urodynamics in the diagnostic work up of SUI has been discussed in the SUI Section of this guideline.

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The use of techniques to reduce the POP during urodynamic evaluation in order to diagnose occult SUI is common practice. This information may be used to decide if additional anti-UI surgery should be offered at the time of POP surgery or to counsel patients on the possible after-effects of POP treatment. There are several POP reduction methods that may be used during physical examination or urodynamic evaluation. In a multicentre observational study, five different cough/stress tests were compared for their ability to detect SUI in women with POP [633]. Stress urinary incontinence during at least one of the five tests occurred in 60/205 (29.2%) of women without SUI symptoms. Looking at single test performance, the detection rate of occult SUI in women without SUI symptoms increases from 4.4% in case of no reduction, to 22% in case of reduction with a pessary. A large randomised trial which included women with POP without symptoms of SUI, who were randomised to sacrocolpopexy with or without Burch colposuspension [634]. Three hundred and twenty two stress-continent women with stages 2–4 prolapse underwent standardised urodynamic testing, and the protocol included five prolapse reduction methods. Pre-operatively, 12 of 313 (3.7%) women demonstrated urodynamic SUI without prolapse reduction. Pre-operative detection of urodynamic SUI with prolapse reduction at 300 mL was by pessary, 6% (5 of 88); manual, 16% (19 of 122); forceps, 21% (21 of 98); swab, 20% (32 of 158); and speculum, 30% (35 of 118). Another large trial included women with POP without SUI symptoms randomised to vaginal POP surgery with or without (sham incision) MUS [635]. Before surgery, 33.5% (111/331) of women demonstrated SUI at a prolapse-reduction cough stress test. In an observational study of 172 women with POP without SUI, 19% of women were diagnosed with occult SUI on basic office evaluation (with prolapse reduction with swab on forceps) and 29% on urodynamic evaluation [636]. In summary, SUI can be demonstrated in women with POP without symptoms of SUI after POP reduction in up to 30% of cases. There is no consensus on the best reduction technique. Although the detection rate of occult SUI increases after reduction of POP in SUI-symptom-negative women, its clinical value is under debate. In one trial, pre-operative stress continent women were evaluated during urodynamic testing with prolapse reduction to determine if they were more likely to report post-operative SUI, regardless of concomitant colposuspension (controls 58% vs. 38% [p = 0.04] and Burch 32% vs. 21% [p = 0.19]) [634]. In another trial, women with SUI during the cough stress test after POP reduction reported UI at 3 months in 29.6% in the sling group, compared with 71.9% in the sham group (adjusted OR: 0.13) [635]. Women with a positive prolapsereduction stress test before surgery appeared to receive more benefit from a sling at 3 months, but not at 12 months, than did those with a negative test. In a large observational study women did not receive additional anti-UI surgery even if they had SUI after POP reduction pre-operatively. In this scenario 9% (16/172) of all women developed post-operative SUI and six women (4%) underwent surgery for de novo SUI [636]. Women with demonstrable pre-operative SUI were more at risk of post-operative SUI: 28% vs. 5% (diagnostic OR: 7). Based on urodynamic evaluation only, one more woman was predicted to have post-operative SUI, but all 6 women who underwent treatment for de novo SUI showed SUI during basic office evaluation. In a model developed to predict the risk of de novo SUI in women undergoing POP surgery based on findings from two trials, a total of 12 pre-operative predictors were tested [637]. A positive finding of SUI during a preoperative prolapse reduction test was included in this model, but it failed to be of significant predictive value as a single item. In addition, pre-operative POP stage was not associated with the risk of de novo SUI. 4.7.3.1

Summary of evidence and recommendation for the detection of SUI in women with POP

Summary of evidence POP reduction during cough stress test, in office or during UDS, will detect SUI in approximately 30% of continent women. Women with SUI after POP reduction pre-operatively (occult SUI) are likely to be at increased risk of developing SUI symptoms after POP surgery.

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Recommendation Perform a pelvic organ prolapse (POP) reduction test in continent women to identify those with occult stress urinary incontinence and counsel them about the pros and cons of additional anti-incontinence surgery at the time of POP surgery.

Strength rating Strong

4.7.3.2 Urodynamics in women with POP and LUTS (without stress urinary incontinence). The role of urodynamics is less clear in women presenting with POP and concurrent LUTS, other than SUI. Pelvic organ prolapse is a complex condition incorporating not only different compartments of the vagina, but also presenting at different stages in terms of severity. Information about detrusor activity, as assessed with urodynamics, may provide information about the risk of developing DO after surgery, but also on the risk of urinary retention due to DU. An observational study assessed predictors for DO following POP surgery for POP-Q stage 3 or higher in 1,503 women and the authors concluded that a pre-operative maximum urethral closure pressure of ≥ 60 cm H2O, a Qmax of < 15 mL/sec, a maximum detrusor voiding pressure (Dmax) ≥ 20 cm H2O and a PVR volume of ≥ 200 mL were independent risk factors for post-operative DO [638]. A small observational study (n = 49) evaluated those with pre-operative DU (detrusor pressure at maximum flow was ≤ 10 cm H2O and Qmax of ≤ 12 mL/s) after POP surgery. Surgery objectively “cured” DU in 47% of women and urodynamic findings normalised after surgery [639]. The 2019 NICE Guidelines do not include a recommendation to perform urodynamics as part of the diagnostic workup of POP, except for the combination with symptomatic SUI [67]. 4.7.4 Disease management Pelvic organ prolapse symptoms can be treated with PFMT, vaginal pessary use, surgery or a combination of these treatments. The scope of this guideline is to focus on LUTS in women and therefore only data on the effect of treatment of urinary symptoms are presented. 4.7.4.1 Conservative treatment of pelvic organ prolapse The 2013 NICE guideline on Urinary Incontinence and Pelvic Organ Prolapse in Women updated its management section in 2019, including a full evidence review [67]. The overall conclusion with respect to conservative treatment for POP was that the evidence is of low quality. A total of 13 RCT’s were identified. Seven studies presented data on changes in urinary symptoms [640-646]. An additional search identified 4 RCT’s that addressed the addition of PFMT to POP surgery [647-650], and one that compared combined PFMT/Pilates therapy with lifestyle advice by leaflet [651]. Five studies [641, 643-645, 651] compared PFMT to lifestyle advice/leaflet, one study [642] compared PFMT to PFMT with pessary, one study [646] PFMT to pessary therapy, and five studies compared surgery for POP with or without the addition of PFMT [640, 647-650]. 4.7.4.1.1 Pelvic floor muscle training versus lifestyle advice An RCT (n = 109) reported that at 6 months follow-up the ICIQ-UI-SF scores improved in favour of the PFMT group compared with a control group receiving lifestyle advice only (difference from baseline PFMT 2.40 points and control 0.2 points, p = 0.002) [641]. However, the difference of 2.4 points from baseline, in favour of PFMT, has to be viewed with caution as the mean baseline score in the PFMT group was higher compared to the control group (7.4 vs. 5.9, p = 0.05). Likewise, it has to be noted that the absolute ICIQ-UI-SF values at 6 months follow-up were not significantly different between groups (PFMT 4.8 vs. control 5.2). Two publications from one RCT reported on the 3, 6 and 12 month results of lifestyle advice only vs. lifestyle advice combined with group PFMT [643, 644]. The UDI-6 and UIQ-7 questionnaires were used to assess urinary symptoms. At 3 months follow-up both groups (53 women in the lifestyle group and 56 in the lifestyle + PFMT cohort) reported significantly improved UDI-6 scores whilst the lifestyle-only group also reported significantly greater improvement on the UIQ-7. Between-group comparison showed no differences in UDI-6 and UIQ-7 scores at 6 months. At 12 months follow-up, the majority of women had sought additional treatment (70% in the lifestyle-only group and 48% in the lifestyle/PFMT group, p = 0.05). The number of patients remaining on the original therapy was too small to reach strong conclusions. One RCT reported on the 6 and 12 months follow-up of 225 women with POP-Q stage 1–3 randomised to individualised PFMT and 222 women randomised to lifestyle leaflet information only (control) [645]. Urinary symptoms were assessed with a single question on the existence of UI, a single question regarding the need to strain to void and a single question regarding incomplete bladder emptying which were supplemented with the ICIQ-SF questionnaire score. At 6 months, significantly more women in the control group reported UI, the need to strain to empty bladder and the feeling of incomplete emptying compared to the PFMT group. The score on

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the ICIQ-SF was also significantly worse in the control group as compared to the PFMT group. However, at 12 months there was no significant difference on these items between groups. It has to be noted that 50% in the control group received additional treatment within the 12-month study period. Twenty-seven percent had additional PFMT, which may have had an effect on the 12-month data. Another RCT reported on the 24-month follow-up of 414 women with stage 1–3 POP (207 assigned to PFMT/ Pilates and 207 to lifestyle advice) [651]. Urinary symptoms were assessed with the ICIQ-UI-SF and a question about UI and difficulty emptying the bladder. At 24 months the ICIQ-UI-SF score was significantly better in the intervention group (mean difference -0.83, p = 0.008). However, the proportion of women reporting any UI did not differ between groups, nor did the number of pads used weekly. 4.7.4.1.2 Pelvic floor muscle training versus pelvic floor muscle training with pessary One RCT compared PFMT alone to PFMT and pessary therapy for symptomatic POP [642]. Urinary tract symptom changes were assessed using the Urogenital Distress Inventory-6 (UDI-6) and the Urinary Impact Questionnaire (UIQ) at 6 and 12 months follow-up. At 12 months follow-up there was no difference in the between-group comparison. With respect to the UIQ, women in the pessary/PFMT showed a significant improvement from baseline, but the PFMT-only group did not. Women in the pessary/PFMT group reported significantly more frequent de novo SUI (48% vs. 22%), and also more improvement of pre-existing voiding difficulty (62.5% vs. 35.5%). 4.7.4.1.3 Pelvic floor muscle training versus pessary only One RCT reported on the 24-month follow-up of 82 women with symptomatic POP randomised to pessary therapy and 80 women randomised to PFMT [652]. The UDI-6 was used as the outcome measure for urinary symptoms. Both in the ITT and per protocol analyses the UDI score did not differ significantly between groups at 24 months of follow-up. 4.7.4.1.4 Surgery versus surgery with pelvic floor muscle training An assessor-blinded RCT compared surgery for POP with or without additional pre-and post-operative PFMT. At 12 months after surgery there were no significant differences between groups on the change in scores of the UDI nor the IIQ scores [640]. Another RCT reported on the 6-month follow-up of 57 women (28 surgery/29 surgery with PFMT). The UDI-6 was used to assess urinary symptoms. There was a statistically significant improvement on the UDI-6 score for both groups, but not between groups [648]. Another RCT reported on the results of a 2x2 factorial design in which women were first randomised between two surgical techniques for POP and in addition between additional PFMT (n = 188) or not (n = 186) [649]. The UDI was used to assess urinary symptoms up to 24 months. No significant differences were found between the addition of PFMT to surgery or not. Another study of the same population reported on SUI in particular [650]. and no significant differences were found between women who had additional PFMT and those who had not. Finally, in 2020 an RCT reported on the 40 and 90 days follow-up of 48 women randomised to supervised PFMT before and after surgery and 40 women having surgery only [647]. The UDI-6 was used to assess urinary symptoms. No statistically significant differences in UDI-6 scores were identified at 40 and 90 days. The NICE guideline on the management of POP advocates considering supervised PFMT for at least 16 weeks as initial treatment for symptomatic prolapse [67]. The use of pessary is also to be considered, alone or combined with PFMT. It is important to recognise that the benefit is expected on typical POP symptoms, like feeling or seeing a bulge out of the vagina, and not on LUTS, as the reported RCTs show. From a urological perspective, initiating conservative treatment for asymptomatic POP in order to treat UI or bladder emptying problems is not supported by the data. 4.7.4.1.5 S  ummary of evidence and guidelines for the conservative treatment of pelvic organ prolapse and lower urinary tract symptoms Summary of evidence Pelvic floor muscle therapy improves LUTS for up to six months in POP patients who do not have additional pessary or surgical treatment. If pessary therapy or surgical intervention is used for POP, PFMT does not show an additional benefit.

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Recommendations Inform women with pelvic organ prolapse (POP), who do not need a vaginal pessary or surgical intervention, about the potential relief from lower urinary tract symptoms (LUTS) from pelvic floor muscle therapy (PFMT). Do not offer pre-operative PFMT in order to improve outcome of LUTS if pessary therapy or surgical intervention is indicated for POP.

Strength rating Strong

Strong

4.7.4.2 Pelvic organ prolapse surgery and overactive bladder Only a few studies specifically address the effect of POP surgery on OAB symptoms. A systematic review of 12 studies, excluding women with SUI, evaluated OAB symptoms before and after surgery [653]. All but one study reported an improvement of OAB symptoms. The same authors performed a prospective analysis of 505 women who had POP surgery with or without mesh [654]. Symptoms were assessed with UDI questions and each symptom was dichotomised into not bothersome or bothersome. Mean follow-up was 12.7 months. The incidence of bothersome urinary frequency reduced from 36.6% to 14.6%, with de novo symptoms occurring in 6.1%. Bothersome urgency symptoms reduced in 36.8% to 12.9% of women, with 5.0% developing de novo symptoms. Urgency UI symptoms reduced from 21.2% to 6.1% of women, with 5.3% developing de novo symptoms. One observational study evaluated frequency and urgency symptoms without consideration of bother in 87 women undergoing POP surgery and showed an improvement in frequency by 75%, and in urgency in 83% [655]. The effect of the POP-Q stage did not seem to influence the effect of surgery on OAB symptoms [654, 655]. Another observational study (n = 43) evaluated the effect of posterior repair on OAB/DO and showed a 70–75% improvement rate in both parameters after surgery [656]. 4.7.4.3 Pelvic organ prolapse surgery and bladder outlet obstruction The criteria for BOO are based on urodynamic assessment. Pelvic organ prolapse can be categorised as anatomical BOO which is addressed in Sections 4.5.2.2 and 4.5.3.1. 4.7.4.4 Pelvic organ prolapse surgery and stress urinary incontinence The aim of this section is to address the options available to women who require surgery for POP and who have associated SUI (either before or after reduction of prolapse), and to assess the value of prophylactic antiUI surgery in women with no evidence of SUI. A systematic review and meta-analysis of ten trials on prolapse surgery with or without an anti-incontinence procedure was reported in 2018 [657]. In addition, a Cochrane review including nineteen trials (n = 2,717) evaluating bladder function after surgery for POP presented analyses of women with POP and SUI, women with POP and occult SUI and women with POP who were continent [658]. 4.7.4.4.1 Vaginal pelvic organ prolapse surgery in women with stress urinary incontinence Two trials addressed post-operative SUI in patients who had been diagnosed with SUI pre-operatively and had vaginal POP surgery [659, 660]. Two trials (n = 185 and n = 134) compared the use of MUS at initial POP surgery to POP surgery alone. The RR for post-operative SUI was 0.30 in favour of the combined POP surgery and MUS group. One of these two trials also compared the use of MUS at initial POP surgery and at 3 months if SUI persisted [659]. At 12 months follow-up there was no difference between the groups regarding post-operative UI (RR: 0.41); however, 44% of the women without initial MUS never required surgery and 29% were dry. 4.7.4.4.2 Abdominal pelvic organ prolapse surgery in women with stress urinary incontinence One RCT randomised 47 women with POP and SUI to an abdominal POP surgical procedure; e.g. sacrocolpopexy with or without Burch colposuspension. Additional SUI surgery did not improve post-operative SUI as compared to sacrocolpopexy alone (RR: 1.38) [661]. This finding remained consistent over 5 years follow-up [662]. Another RCT compared the addition of a MUS or Burch colposuspension to an abdominal sacrocolpopexy in 113 women with POP and SUI [663]. At 2 years follow-up the RR for post-operative SUI was 0.54 in favour of the MUS group. 4.7.4.4.3 Vaginal POP surgery in women with prolapse and occult stress urinary incontinence Five RCTs including a total of 194 women who had vaginal POP repair alone and 174 women who had an additional MUS at the time of primary surgery were identified [635, 664-667]. The RR of post-operative SUI was 0.38 in favour of the MUS group.

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4.7.4.5 Vaginal pelvic organ prolapse surgery in continent women One RCT comparing vaginal POP surgery alone with concomitant MUS in 220 women found that postoperative SUI occurred in 46/113 (40.7%) women who had POP surgery alone, compared to 30/107 (28.0%) who had additional MUS (RR: 0.69) [658]. 4.7.4.5.1 Abdominal pelvic organ prolapse surgery in continent women Two RCTs, compared abdominal sacrocolpopexy with (n = 189) or without (n = 190) Burch colposuspension with an outcome favouring the addition of Burch colposuspension (RR for de novo SUI 0.69) [668, 669]. 4.7.4.6

Adverse events associated with combined pelvic organ prolapse and stress urinary incontinence surgery Data from 6 RCT’s on vaginal POP surgery with MUS were pooled to assess adverse events [635, 659, 660, 665-667]. Urgency UI was less frequent after combination surgery as compared to POP surgery alone (28 vs. 42%, RR: 0.7), but there was a tendency towards more voiding problems. Adverse events directly related to surgery occurred more often in the combination group (28% vs. 15%, RR: 1.8), as did serious adverse events such as bladder perforation, urethral injuries, tape exposure (14% vs. 8%, RR: 1.7) [657]. In summary, it is difficult to generalise the results of trials using different procedures to treat both POP and UI. It seems that with a combined procedure the rate of SUI post-operatively is lower but post-operative voiding symptoms and complication rates are higher. Studies using MUS have generally shown more significant differences in UI outcomes with combined procedures than when other types of anti-UI procedure have been used. It must be taken into account that although more women are dry after combined surgery for POP with MUS, there are potential adverse events that should be balanced against potential benefits. 4.7.5

Summary of evidence and recommendations for surgery in women with both pelvic organ prolapse and stress urinary incontinence

Summary of evidence Women with pelvic organ prolapse and urinary incontinence Surgery for POP and SUI shows a higher rate of cure of UI in the short-term than POP surgery alone. There is conflicting evidence on the relative long-term benefit of surgery for POP and SUI vs. POP surgery alone. Combined surgery for POP + SUI carries a higher risk of adverse events than POP surgery alone. Continent women with pelvic organ prolapse Continent women with pelvic organ prolapse are at risk of developing SUI post-operatively. The addition of a prophylactic anti-UI procedure reduces the risk of post-operative UI but increases the risk of adverse events. Women with pelvic organ prolapse and overactive bladder There is some low-level inconsistent evidence to suggest that surgical repair of POP can improve symptoms of overactive bladder. Recommendations for women requiring surgery for bothersome pelvic organ prolapse (POP) who have symptomatic or occult stress urinary incontinence (SUI) Offer simultaneous surgery for POP and SUI only after a full discussion of the potential risks and benefits of combined surgery vs. POP surgery alone. Inform women of the increased risk of adverse events with combined prolapse and antiurinary incontinence surgery compared to prolapse surgery alone. Recommendations for women requiring surgery for bothersome POP who do not have symptomatic or occult SUI Inform women that there is a risk of developing de novo SUI after prolapse surgery. Warn women that the benefit of combined surgery for POP and SUI may be outweighed by the increased risk of adverse events compared to prolapse surgery alone.

4.8

LE 1a 1a 1a 1a 1a

2b

Strength rating Strong Strong

Strong Strong

Urinary fistula

The evidence relating to diagnosis and treatment of urinary fistulae is generally of low-level and is largely composed of case series and other consensus statements. In particular, the epidemiology, aetiology, diagnosis, treatment and prevention of obstetric and non-obstetric fistulae have been described in detail during the recent ICI conference [670]. Most non-obstetric fistulae are iatrogenic in origin, with the majority caused by pelvic

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surgery (e.g. hysterectomy for benign or malignant conditions, bowel resection, and urological surgery). The risks during pelvic surgery increase relative to the complexity of the resection, the extent of primary disease and the existence of prior radiotherapy (especially for recurrent disease). When a fistula occurs following radiotherapy for primary treatment, this may be an indication of tumour recurrence. 4.8.1 Epidemiology, aetiology and pathophysiology 4.8.1.1 Obstetric fistula According to the WHO, fistulae affect more than two million women, mostly from sub-Saharan African and Asian countries. The pooled prevalence of fistula from population studies is at 0.29/1000 pregnancies [671]. Poor quality obstetric care, staff unaccountability, late referral and poor nursing standards have been identified as health system causes [671]. However, obstructed labours are poorly documented. The main individual risk factors include age at first marriage, short stature, pregnancy with a male child, failure to attend ante-natal care, low socio-economic status, low social class, lack of employment and illiteracy [672-674]. Obstetric fistulae have detrimental consequences on global and individual health and are associated with malnutrition, sexual dysfunction, anxiety, depression, insomnia, social isolation, worsening poverty and suicide [675, 676]. 4.8.1.2 Iatrogenic fistula Poor obstetric care is usually responsible for VVF in the developing world. By contrast, in the developed world, gynaecological or pelvic surgeries are the main causes of VVF. 4.8.1.2.1 Post-gynaecological surgery An injury to the urinary tract during hysterectomy for benign conditions (60–75%), hysterectomy for malignant conditions (30%) and caesarean section (6%) are the main causes of post-operative VVF in the developed world [677, 678]. The risk of pelvic organ fistula following hysterectomy ranges from 0.1 to 4% [679]. Furthermore, fistulae may also occur as a result of primary or recurrent malignancy, or as a consequence of cancer treatment by surgery, radiotherapy, and/or chemotherapy. In a study including 536 women undergoing a radical hysterectomy for invasive cervical cancer, bladder injury occurred in 1.5% with VVF forming in 2.6% and uretero-vaginal fistula (UVF) in 2.4% of cases [680]. Overall, the rate of urogenital fistula appears to be approximately 9 times higher following radical hysterectomy for malignant disease as compared to that following simple hysterectomy (abdominal or vaginal for benign conditions) [681]. Bladder sparing techniques during pelvic exenteration can increase the risk of fistula formation [682]. 4.8.1.2.2 Radiation fistula The risk of fistula seems to be higher for post-operative external radiation (1.9%) compared to intravaginal brachytherapy (0.8%) [683], without any predictive factor being identified [684]. This is most likely due to the heterogeneity of data regarding the tumour type and stage, the form of radiation and the site and dose delivered. 4.8.1.2.3 Rare causes of vesico-vaginal fistula Foreign bodies such as pessaries, sex toys, cups etc. can be a cause of delayed presentation of VVF [685687]. Ketamine abuse has also been shown to be responsible for fistula formation [688]. 4.8.1.3

Summary of evidence for epidemiology, aetiology and pathophysiology of urinary fistula

Summary of evidence The risk of injury to the urinary tract and subsequent fistula formation is higher in women with malignant disease undergoing radical surgery than in women with benign disease undergoing simple surgical procedures. The rate of fistula formation following radiotherapy for gynaecological cancer appears to be of the same order as that following surgical treatment.

LE 2

4

4.8.2 Classification Due to the plethora of VVF classification systems, a consensual classification system needs to be adopted. The Waaldijk and Goh classifications are widely used for diagnosis and follow-up [689-691]. They were originally designed for obstetric fistulae and their use in iatrogenic fistulae is less relevant [692]. Waaldijk’s classification is based on the size and site of the fistula and divides them into 3 main categories - type 1 are VVF with no urethral involvement, type 2 fistulae are those which involve the urethra (and are sub-classified into those with

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circumferential and non-circumferential urethral involvement) and type 3 are fistula involving other parts of the urinary tract. Goh’s classification also uses the presence or absence of urethral involvement to sub-categorise VVF and also takes into account the degrees of fibrosis present. The WHO classification (Table 6) was originally developed for obstetric fistulae and separates fistulae into simple and complex. Table 6: Adapted WHO Classification of fistulae [671]* Simple fistula with good prognosis • Single fistula < 4 cm • Vesico-vaginal fistula • Closing mechanism not involved • No circumferential defect • Minimal tissue loss • Ureters not involved • First attempt to repair

Complex fistula with uncertain prognosis • Fistula > 4 cm • Multiple fistula • Recto-vaginal mixed fistula, cervical fistula • Closing mechanism involved • Scarring • Circumferential defect • Extensive tissue loss • Intravaginal ureters • Failed previous repair • Radiation fistula

*Although this classification was developed for obstetric fistula initially, it could be relevant for iatrogenic fistula as well. 4.8.2.1

Recommendation for the classification of urinary fistula

Recommendation Use a classification system for urinary tract fistulae to try to standardise terminology in this subject area.

Strength rating Strong

4.8.3 Diagnostic evaluation Leakage of urine is the hallmark sign of a urogenital fistula. The leakage is usually painless, may be intermittent if it is position dependent, but more usually is constant. Unfortunately, intra-operative diagnosis of a GU or GI injury is made in only about half of all cases [693]. The diagnosis of VVF usually requires clinical assessment often in combination with appropriate imaging or laboratory studies. Direct visual inspection, cystoscopy, retrograde bladder filling with a coloured fluid or placement of a tampon into the vagina to identify staining may facilitate the diagnosis of a VVF. A double-dye test to differentiate between a UVF and VVF may be useful in some cases [678]. Testing the creatinine level in either the extravasated or collected fluid will confirm fluid leakage as urine. Contrast-enhanced CT with late excretory phase reliably diagnoses urinary fistulae and provides information about ureteric integrity and the possible presence of associated urinoma. Magnetic resonance imaging, in particular with T2 weighting, also provides diagnostic information regarding fistulae [694]. 4.8.4 Management of fistula 4.8.4.1 Management of vesico-vaginal fistula 4.8.4.1.1 Conservative management 4.8.4.1.1.1 Spontaneous closure The reported spontaneous closure rate is 13% ± 23% [695], although this applies largely to small fistulae (size < 1 cm) [670, 696]. Hence, immediate management is usually by urinary catheterisation or diversion; however, within the first two weeks following fistula occurrence, surgical exploration and repair can be considered. 4.8.4.1.1.2 Pharmacotherapies Several case reports describe a successful fistula closure rate following the induction of amenorrhoea by oestrogen, oestrogen/progesterone combinations or luteinising hormone releasing hormone (LHRH) analogues specifically for small (< 7 mm), uretero- or vesico-uterine fistula following caesarean section [697-703]. One RCT comparing the efficacy of using fibrin glue compared to Martius flap inter-positioning (n = 14; < 4 cm and n = 5; > 5 cm) did not report statistically different outcomes between the two types of treatment [704]. 4.8.4.1.1.3 Palliation and skin care During the intervening period between diagnosis and repair, UI pads with the aim of prevention of skin complications related to chronic urinary leakage can be provided and the use of a barrier cream or local oestrogen can also be considered [705, 706].

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4.8.4.1.1.4 Nutrition Nutritional support is essential in patients with fistulae induced by malignant disease or radiotherapy [707], or following diversion surgery [707-709]. 4.8.4.1.1.5 Physiotherapy Early involvement of the physiotherapist in pre-operative management and rehabilitation of fistula patients suffering from limb weakness, foot drop and limb contracture is essential [710, 711]. 4.8.4.1.1.6 Antimicrobial therapy Active infection in the genital or urinary tracts should be treated prior to surgical repair [712]. 4.8.4.1.1.7 Counselling Confident and realistic counselling by the surgeon is essential and the involvement of nursing staff or counsellors with experience of fistula patients is also highly desirable. 4.8.4.1.2 Surgical management 4.8.4.1.2.1 Timing of surgery Findings from uncontrolled case series suggest no difference in success rates for early (within 3 weeks) or delayed (after 3 months) closure of VVF. 4.8.4.1.2.2 Surgical approaches Vaginal procedures There are two main types of closure techniques applied to the repair of urinary fistulae, the classical saucerisation/partial colpocleisis [695] and the more commonly used dissection and repair in layers or ‘flapsplitting’ technique [713]. There are no data comparing their outcomes. Abdominal procedures Repair by the abdominal route is indicated when high fistulae are fixed at the vaginal vault and are inaccessible via a vaginal approach. A transvesical repair has the advantage of being entirely extraperitoneal. A simple transperitoneal repair is used less often although it is favoured by some using the laparoscopic approach. A combined transperitoneal and transvesical procedure may be utilised for fistula repair following Caesarean section. There are no RCTs comparing abdominal and vaginal approaches. Results of secondary and subsequent repairs are not as successful as the initial repair [714]. A single RCT compared trimming of the fistula edge with no trimming and found no difference in success rates but failed repairs in trimmed cases ended up with larger recurrences than untrimmed cases, which were smaller [715]. Laparoscopic and robotic procedures Very small series (single figures) have been reported using these techniques, but whilst laparoscopic repair is feasible with and without robotic assistance, it is not possible to compare outcomes with alternative surgical approaches. Tissue interposition Tissue flaps are often added as an additional layer of repair during VVF surgery. Most commonly, such flaps are utilised in the setting of recurrence after a prior attempt at repair, for VVF related to previous radiotherapy (described later), ischaemic or obstetric fistulae, large fistulae, and finally those associated with a difficult or tenuous closure due to poor tissue quality. However, there is no high-level evidence that the use of such flaps improves outcomes for either complicated or uncomplicated VVF. Post-operative management There is no high-level evidence to support any particular practice in post-operative management but most reported series used catheter drainage for at least ten days and longer periods in complex or radiationassociated fistulae (up to three weeks). The performance of post-operative cystogram prior to catheter removal can miss a persistent fistula if not done with a micturition phase or if the fistula is located at the bladder neck. 4.8.4.1.3 Management of complications of vesico-vaginal fistulae The complications of VVF repair are varied and can include: • •

Persistence or recurrence of fistula; Persistence or recurrence of UI;

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• • • • • • • • • • •

Persistence of LUT symptoms or occurrence of new LUT symptoms, including de novo OAB symptoms and/or SUI; Infections: wound and UTIs/urosepsis; Ureteric obstruction (ligation, fibrosis, injury); Bladder outlet obstruction (meatal stenosis, urethral stricture, bladder neck obstruction); Bladder contracture; Vaginal stenosis; Sexual dysfunction (vaginismus/dyspareunia); Rare complications (granulomas/diverticulum formation); Neurological complications (foot drop/neurogenic bladder); Psychological trauma (social isolation/divorce/mental illness); Infertility.

The literature on the treatment and management of complications of fistula repairs is extremely scarce and is mostly experience-based. It is impossible to give any specific evidence-based guidance. 4.8.4.2 Management of radiation fistulae Modified surgical techniques are often required, and indeed, where the same techniques have been applied to both surgical and post-radiation fistulae, the results from the latter have been consistently poorer [716]. Due to the wide field abnormality surrounding many radiotherapy-associated fistulae, approaches include, on the one hand, permanent urinary and/or faecal diversion [716, 717] or alternatively preliminary urinary and faecal diversion, with later undiversion in selected cases following reconstruction. In cases where life expectancy is deemed to be very short, ureteric occlusion might be more appropriate. 4.8.4.3 Management of ureteric fistulae 4.8.4.3.1 General principles Patients at higher risk of ureteric injury require experienced surgeons who can identify and protect the ureter and its blood supply to prevent injury and also recognise injury promptly when it occurs. Immediate repair of any intra-operative injury should be performed observing the principles of debridement, adequate blood supply and tension-free anastomosis with internal drainage using stents [718]. Delayed presentation of upper tract injury should be suspected in patients whose recovery after relevant abdominal or pelvic surgery is slower than expected, if there is any fluid leak, and if there is any unexpected dilatation of the pelvicalyceal system. Whilst there is no evidence to support the use of one surgical approach over another, there is consensus that repair should adhere to the standard principles of tissue repair and safe anastomosis, and be undertaken by an experienced team. Conservative management is possible with internal or external drainage, endoluminal management using nephrostomy and stenting where available, and early (< two weeks) or delayed (> three months) surgical repair when required [719]. Functional and anatomical imaging should be used to follow up patients after repair to guard against development of ureteric stricture and deterioration in renal function. 4.8.4.3.2 Uretero-vaginal fistulae Uretero-vaginal fistula occurring in the early post-operative phase predominantly after hysterectomy is the most frequent presentation of UUT fistulae in urological practice. An RCT in 3,141 women undergoing open- or laparoscopic gynaecological surgery found that prophylactic insertion of ureteric stents made no difference to the low risk (1%) of ureteric injury [720]. Endoscopic management is sometimes possible by retrograde stenting, percutaneous nephrostomy and antegrade stenting if there is pelvicalyceal dilatation, or ureteroscopic realignment [721]. However, the longterm success rate is unknown. If endoluminal techniques fail or result in secondary stricture, the abdominal approach to repair is standard and may require end-to-end anastomosis, re-implantation into the bladder using psoas hitch or Boari flap, or replacement with bowel segments with or without reconfiguration. As a last resort, nephrectomy may be considered, particularly in the context of a poorly functioning kidney and an otherwise normal contralateral kidney [722-726]. 4.8.4.3.3 Management of urethrovaginal fistulae 4.8.4.3.3.1 Aetiology Whilst they are rare, most urethrovaginal fistulae in adults have an iatrogenic aetiology. Causes include surgical treatment of SUI with bulking agents or synthetic slings, surgery for urethral diverticulum and genital reconstruction in adults. Irradiation and even conservative treatment of prolapse with pessaries can lead to the formation of fistulae.

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4.8.4.3.3.2 Diagnosis Clinical vaginal examination, including the three-swab test, is often sufficient to diagnose the presence of a urethrovaginal fistula. Urethroscopy and cystoscopy can be performed to assess the extent and location of the fistulae. In cases of difficult diagnosis, VCUG or US can be useful. 3D-MRI or CT scan is becoming utilised more widely to clarify anatomy [727, 728]. 4.8.4.3.3.3 Surgical management Choice of surgery will depend on the size, localisation and aetiology of the fistula and the amount of tissue loss. Principles of reconstruction include identifying the fistula, creation of a plane between vaginal wall and urethra, watertight closure of urethral wall, eventual interposition of tissue, and closure of the vaginal wall. One case series reports that a vaginal approach yielded a success rate of 70% at first attempt and 92% at second attempt, and that an abdominal approach only leads to a successful closure in 58% of cases [729]. A vaginal approach required less operating time, had less blood loss and a shorter hospitalisation time. Most authors describe surgical principles that are identical to those of vesico-vaginal fistula repair: primary closure rates of 53-95.4% have been described. A series of 71 women, treated for urethra-vaginal fistula reports 90.1% of fistulae were closed at the first vaginal intervention. Additionally, 7.4% were closed during a second vaginal intervention. Despite successful closure, SUI developed in 52%. The stress incontinent patients were treated with synthetic or autologous slings and nearly 60% became dry and an additional 32% improved. Urethral obstruction occurred in 5.6% and was managed by urethral dilation or urethrotomy [730]. 4.8.4.3.3.4 Flaps and neo-urethra The simplest flap is a vaginal advancement flap to cover the urethral suture line. Labial tissue can be harvested as a pedicled skin flap. This labial skin can be used as a patch to cover the urethral defect, but can also be used to create a tubular neo-urethra [731, 732]. The construction of a neo-urethra has mostly been described in traumatic aetiologies. In some cases a transpubic approach has been used [733]. The numbers of patients reported are small and there are no data on the long-term outcome of fistula closure and continence rates. The underlying bulbocavernosus tissue can be incorporated in the pedicled flap and probably offers a better vascularisation and more bulking to the repair. This could allow a safer placement of a sling afterwards, in those cases where bothersome SUI would occur post-operatively [734, 735]. 4.8.4.3.3.5 Martius flap While in obstetrical fistula repair it was not found to have any benefit, in a large retrospective study in 440 women the labial bulbocavernosus muscle/fat flap by Martius is still considered by some to be an important adjunctive measure in the treatment of GU fistulae where additional bulking with well-vascularised tissue is needed [736]. The series of non-obstetrical aetiology are small and all of them are retrospective. There are no prospective data, nor randomised studies [737]. The indications for Martius flap in the repair of urethro-vaginal fistulae remain unclear. 4.8.4.3.3.6 Rectus muscle flap Rectus abdominis muscle flaps have been described by some authors [738, 739]. 4.8.4.3.3.7 Alternative approaches An alternative retropubic retro-urethral technique has been described by Koriatim [740]. This approach allows a urethro-vesical flap tube to be fashioned to form a continent neo-urethra. 4.8.4.4

Summary of evidence and recommendations for the management of urinary fistula

Summary of evidence Spontaneous closure of surgical fistulae does occur, and appears more likely for small fistulae although it is not possible to establish the rate with any certainty. There is no evidence that the timing of repair makes a difference to the chances of successful closure of a fistula. There is no high-quality evidence of differing success rates for repair of vesico-vaginal fistulae by vaginal, abdominal, transvesical and transperitoneal approaches. A period of continuous bladder drainage may be crucial to successful fistula repair but there is no high-level evidence to support one regimen over another. A variety of interpositional grafts can be used in either abdominal or vaginal procedures, although there is little evidence to support their use in any specific setting.

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LE 3 3 3 3 3

97

Post-radiation fistula Successful repair of irradiated fistulae may require prior urinary diversion and the use of non-irradiated tissues to effect repair. Ureteric fistula Prophylactic ureteric stent insertion does not reduce risk of ureteric injury during gynaecological surgery. Antegrade endoluminal distal ureteric occlusion combined with nephrostomy tube diversion often palliates urinary leakage due to malignant fistula in the terminal phase. Urethro-vaginal fistula Urethro-vaginal fistula repair may be complicated by SUI, urethral stricture and urethral shortening which may necessitate long-term follow-up. Recommendations General When reporting on outcomes after fistula repair, authors should make a clear distinction between fistula closure rates and post-operative urinary incontinence (UI) rates and the time at which the follow-up was organised. Do not routinely use ureteric stents as prophylaxis against injury during routine gynaecological surgery. Suspect ureteric injury or fistula in patients following pelvic surgery if a fluid leak or pelvicalyceal dilatation occurs post-operatively, or if drainage fluid contains high levels of creatinine. Use three-dimensional imaging techniques to diagnose and localise urinary fistulae particularly in cases with negative direct visual inspection or cystoscopy. Manage upper urinary tract fistulae initially by conservative or endoluminal techniques where such expertise and facilities exist. Surgical principles Surgeons involved in fistula surgery should have appropriate training, skills, and experience to select an appropriate procedure for each patient. Attention should be given as appropriate to skin care, nutrition, rehabilitation, counselling and support prior to, and following, fistula repair. Tailor the timing of fistula repair to the individual patient and surgeon requirements once any oedema, inflammation, tissue necrosis, or infection, are resolved. Ensure that the bladder is continuously drained following fistula repair until healing is confirmed (expert opinion suggests: 10–14 days for simple and/or postsurgical fistulae; 14–21 days for complex and/or post-radiation fistulae). Where urinary and/or faecal diversions are required, avoid using irradiated tissue for repair. Use interposition graft when repair of radiation-associated fistulae is undertaken. Repair persistent uretero-vaginal fistulae by an abdominal approach using open, laparoscopic or robotic techniques according to availability and competence. Urethro-vaginal fistulae should preferably be repaired by a vaginal approach.

4.9

3

2 4

3

Strength rating Strong

Strong Strong

Weak Weak

Weak Weak Weak Weak

Weak Weak Weak Weak

Urethral diverticulum

A female urethral diverticulum is a sac-like protrusion composed of the entire urethral wall or only by the urethral mucosa, situated between the peri-urethral tissues and the anterior vaginal wall. 4.9.1 Epidemiology, aetiology, pathophysiology Urethral diverticulum is an uncommon condition with a prevalence estimated to range between 1 and 6%. Amongst women with LUTS attending a tertiary referral centre one study reported a prevalence of up to 10% [741]. However, as many patients are asymptomatic or misdiagnosed, the true incidence is unknown [742-744]. Given the rarity of the condition, most published series are small and single institutional. Urethral diverticulum are thought to arise from repeated obstruction, infection and subsequent rupture of periurethral glands into the urethral lumen, resulting in an epithelialised cavity that communicates with the urethra [742]. Iatrogenic damage to the urethra may also play a role, as up to 20% of women with urethral diverticula are noted to have a history of prior urethral surgery, dilation, or traumatic delivery [742, 745]. Iatrogenic urethral diverticula formation associated with synthetic suburethral sling has also been reported [746-748].

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4.9.2

Classification

Table 7: Classification system for female urethral diverticula based on characteristics* Localisation

Configuration

Communication

Continence

Mid-urethral Distal Proximal Full length Single Multiloculated Saddle shaped Mid-urethral No communication visualised Distal Proximal Stress urinary incontinence Continent Post-void dribble Mixed incontinence

*Limited LNS C3 classification of urethral diverticula [745, 749, 750]. 4.9.3 Diagnosis The commonly encountered symptoms for urethral diverticulum such as pain, urgency, frequency, recurrent UTIs, vaginal discharge, dyspareunia, voiding difficulties or UI [751], are common to many other LUT dysfunctions. Consequently, there is no pathognomonic cluster of symptoms to identify urethral diverticula. Many patients with urethral diverticula are asymptomatic. However, urethral diverticulum often presents with a palpable urethral mass. It may be possible to express a purulent exudate from the urethra. Occasionally a stone may develop within the diverticulum. The diagnosis of a urethral diverticulum may be achieved by physical examination, VCUG and MRI. Other investigations include urethrocystoscopy, endocavitary (often transvaginal or sometimes transurethral) pelvic floor US and double balloon urethrography. No robust diagnostic accuracy studies address the question of the best test to confirm the diagnosis in a woman with a clinical suspicion of urethral diverticulum. However, a case series of 27 patients concluded that endoluminal (vaginal or rectal) MRI has better diagnostic accuracy than VCUG [752] and determines the size and extent of urethral diverticula more accurately. In a case series of 60 subjects, it was reported that the sensitivity, specificity, positive predictive value and negative predictive value of MRI is 100%, 83%, 92% and 100%, respectively [753]. Another case series reported 100% specificity and sensitivity of MRI in 60 patients [754]. However, in a case series of 41 patients, authors reported a 25% discrepancy between MRI and surgical findings [755]. Endoluminal MRI with either a vaginal or rectal coil may provide even better image quality than simple MRI [756]. Magnetic resonance imaging is the gold standard for the diagnosis and planning surgical repair. Magnetic resonance imaging also proved to be useful in diagnosing inflammation or tumour in the diverticulum [757, 758]. Urethrocystoscopy can be used to visualise the ostia of the diverticulum. Knowledge of the ostia’s location and number can assist with surgical planning since each of these ostia need to be closed after diverticulectomy. However, given the challenges of urethroscopy in females the ostia is only seen in 42% of cases [751]. If a VCUG is performed antero-posterior and lateral images are required to optimally characterise the configuration of the diverticulum. There is a high risk of false negatives since the ostia of the diverticulum must be patent and the patient must be able to void during the study. In more complex diverticulum where there is septation, the entire diverticula may not be visualised underestimating its complexity or size [759]. The sensitivity of VCUG is 73.5% which is significantly worse than MRI [751]. Ultrasound can be performed transabdominally, transvaginally or transperineally to identify the diverticulum. In particular the transvaginal approach US allows imaging of the urethra from the meatus to the bladder neck in several planes and can identify the number, size, location and contents of the diverticulum. This technique is

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challenging and requires a skilled ultrasonographer. In addition, the probe can compress the urethra, causing distortion [759]. A meta-analysis reported that US of any kind had a sensitivity of 82.0% which was inferior to MRI [759]. However a recent publication on translabial US reported a sensitivity of 95% [760]; therefore, this approach may be explored further by researchers in the future. For patients who cannot have an MRI and the ostia is not seen on cystoscopy, double balloon urethrography can be an option. Modern series have reported a 94.7% sensitivity which is comparable to that of MRI. The technique uses positive pressure to force contrast into the diverticular sac between two balloons; one placed in the bladder and one outside the ostia of the diverticulum. It is technically difficult to achieve a seal sufficient to create a closed urethral space and avoid contrast leaking around the catheter. The procedure can be painful for the patient and carries a risk of UTI. An experienced radiologist is required as well as specialised equipment. Given the current popularity of other imaging modalities many units may not have access to this technique [759]. 4.9.3.1 Associated voiding dysfunction Although the presentation of urethral diverticulum is often non-specific and variable, urethral diverticula can be associated with voiding dysfunction and SUI or UUI. One recent series reported SUI occurring in 60% of patients with urethral diverticulum [761]. A urethral diverticulum is most often located at the level of the mid-urethra. This location often overlaps with the external sphincter. However urethral diverticulum may also extend proximally toward the bladder neck in the vicinity of the proximal sphincter mechanism. This morphology may, in part, explain the association between urethral diverticulum and SUI with potentially more proximal lesions at risk for post-operative SUI [762]. Urethral diverticulum may also be associated with BOO due to the mass effect of the urethral diverticulum, urinary retention, or urgency and UUI [763]. Pain and dysuria associated with urethral diverticulum may also result in acquired voiding dysfunction. Pressure flow studies may have a role in the pre-operative assessment of patients with urethral diverticula and coexisting voiding dysfunction or SUI [744, 764-766]. Indeed, urodynamics may evaluate for coexisting detrusor dysfunction or document the presence or absence of SUI or obstruction prior to repair [767, 768]. Urethral pressure profilometry has also been used in the assessment or diagnosis of urethral diverticulum noting a biphasic pattern, or pressure drop at the level of the lesion during the study [764, 766, 769]. Videourodynamics may be helpful in differentiating SUI from paradoxical UI due to fluid accumulation in the urethral diverticulum. In addition, resting and straining images obtained during fluoroscopic imaging may document an open bladder neck at rest. This may be a consideration in some patients with an extensive urethral diverticulum at the level of the mid-urethra and potential implications for post-operative UI due to compromise of both sphincter mechanisms. 4.9.4 Disease management For women with minimal symptoms who would prefer to avoid invasive treatment, conservative management can be considered. Patients should be warned of the small risk of cancer (1–6%) within the diverticulum [770, 771]. 4.9.4.1 Surgical treatment No RCTs were found to inform regarding the relative effectiveness of available surgical treatments in a woman who has a bothersome urethral diverticulum. Thorough evaluation of the anatomy of the diverticulum is essential in planning reconstructive surgery. There are three surgical approaches to diverticulum: marsupialization, endoscopic incision, and curative treatment with diverticulectomy. Surgical removal is the most commonly reported treatment in contemporary case series. The principles of successful transvaginal diverticulectomy are to: dissect a well vascularised vaginal flap, preserve the periurethral fascia for closure, remove all the diverticular wall, excise the ostia and close the urethra in a watertight fashion, close the incision in a multi-layered fashion with no overlapping suture lines, and preservation or creation of continence. The decision to use a labial fat pad flap, commonly known as a Martius flap, is variable and used more frequently in the following situations: recurrent cases, large urethral defects or for deficient vaginal flaps for

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closure [745, 749] transection of the urethra required for access to a circumferential diverticulum [758] or in the case of complex configuration [763], and if there is a planned future sling procedure required for UI to facilitate the dissection at that time [745]. Marsupialisation involves incision into the mass on the vaginal side to drain the infected contents. The wall is then sutured open with absorbable suture to allow drainage and prevent reaccumulation of infectious materials. This approach leaves the cystic structure in place and can theoretically cause a urethra-vaginal fistula since there is communication with the diverticular ostia, but it is a rapid procedure with little dissection required. This approach has been advocated in the pregnant patient to decompress the diverticulum to allow safe vaginal delivery. A small case series suggests that 75% pregnant women with urethral diverticula managed expectantly end up requiring postpartum surgery [772]. Endoscopic incision is a rarely reported treatment option [773, 774]. This procedure involves finding the narrow neck of the ostia and incising it with a resectoscope. This unroofing of the diverticulum transforms the narrow communication with the urethra that causes symptoms when it gets obstructed into a wide mouthed sac that drains freely. 4.9.4.2 Management of concomitant stress urinary incontinence Many women present with concomitant SUI and urethral diverticula, and may request both conditions to be simultaneously treated. A meta-analysis reports that diverticulectomy actually cured the SUI even without a concomitant anti-incontinence procedure, but no data regarding symptom severity was given and it could be assumed that many of these cured patients had more minimal UI before surgery [751]. Therefore, additional surgical corrections may be required [762, 774]. However, there is no consensus on appropriate timing of surgical management of these two conditions. Thus, patients with symptomatic, bothersome SUI in association with urethral diverticulum may be offered simultaneous anti-UI surgery. Although historical series have shown good results with concomitant bladder neck suspension [768], more contemporary series have utilised pubovaginal fascial slings in patients with satisfactory outcomes [775-778]. Mid-urethral synthetic slings are not recommended as a concomitant anti-UI procedure at the time of urethral diverticulectomy [779]. Synthetic material adjacent to a fresh suture line following diverticulectomy in the setting of potentially infected urine may place the patient at higher risk for subsequent urethral erosion and vaginal extrusion of the sling material, as well as urethrovaginal fistula formation and foreign body granuloma formation. Transvaginal urethral diverticulectomy has a high success rate (defined by being dry) of between 84% and 98%, with a re-operation rate of 2–13% after primary repair during a mean follow-up of 12–50 months [742, 745, 762, 780]. The resolution of symptoms after surgery has been reported to reach 68.8% but less than half of studies comment on symptom improvement [781]. One case series reported rates of storage symptoms decreased significantly post-operatively from 60% to 16% following urethral diverticulum surgery [762]. Other series with long-term follow-up, however, have demonstrated rates of post-operative urgency of 54% [782], and de novo UUI in 36% of patients [774]. Such symptoms post-operatively may indicate urethral diverticulum persistence, urethral diverticulum recurrence, or de novo OAB syndrome or urethral obstruction. Early common post-operative complications include: UTI (0–39%), de novo SUI (3.8–33%), and de novo urinary retention (0–9%), especially in the setting of concomitant placement of an autologous pubovaginal sling [742, 745, 762, 780]. Delayed complications such as urethral stricture are reported in 0–5.2% of cases [742, 745, 774, 780]. Urethrovaginal fistula is a devastating complication presenting in 0.9–8.3% of cases [783]. A distal fistula located beyond the sphincteric mechanism can present with split urinary stream or vaginal voiding and may not require repair. However, a fistula located anywhere from the mid-urethra to the bladder neck may result in UI. These patients should undergo repair with consideration of an adjuvant tissue flap, such as a Martius flap, to aid in closure. The timing of the fistula repair is not well defined, with a delay of 3–6 months after the initial repair generally being a good balance between patient discomfort and optimal tissue quality. Rare complications include: distal urethral necrosis, bladder injury, urethral injury, ureteric injury, and vaginal scarring or narrowing with consequent dyspareunia [783]. One case series reported a recurrence rate of 33% in U-shaped and of 60% in circumferential diverticulum within one year [749], Ingber et al. found a 10.7% recurrence rate in 122 women undergoing diverticulectomy, with a higher risk of recurrence in those with proximal or multiple diverticula or after previous pelvic surgery [782] or radiation. A recurrent urethral diverticulum following initial successful urethral diverticulectomy may occur as a result of a new infection or traumatic insult such as childbirth, a new urethral diverticulum, or recurrence of the original lesion. Recurrence of urethral diverticulum may be due to incomplete removal of the urethral diverticulum, inadequate closure of the urethra or residual dead space (circumferential diverticula), or

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other technical factors. Repeat urethral diverticulectomy surgery represents a unique challenge due to altered anatomy, scarring, and difficulty identifying proper anatomical planes. Stress UI can be worsened or occur de novo after diverticulectomy. This is most likely due to sphincteric damage from the dissection or scarification preventing urethral closure. De novo SUI (10.6% of women) seems to be more common in proximal and in large size (> 30 mm) diverticula [762]. However, Lee et al. noted at least some de novo SUI in 49% of patients following urethral diverticulectomy, the majority of which was minor and did not require additional therapy [784]. Only 10% of these individuals underwent a subsequent SUI operation. Treatment for SUI after a diverticulectomy is not well described in the literature. The most commonly reported surgery is an autologous pubovaginal sling [773] followed by retropubic suspension [774] however there are two cases reported of synthetic mesh sling to treat the SUI without mesh complications [749, 762], but this is certainly controversial. 4.9.4.3 Pathological findings Most urethral diverticula are lined with squamous cells, urothelium or columnar epithelium [745, 785, 786]. In this meta-analysis there is a high prevalence of chronic or acute inflammation (68.6%) and the most commonly reported lesions are nephrogenic metaplasia which occurs in 8%. Diverticula may undergo neoplastic alterations (6%) including invasive adenocarcinomas [787], followed by squamous cell carcinoma in 0.7%. It is unknown if the diverticulum forms first and then transforms into a malignancy or if the malignancy develops first. These malignancies are treated in a similar fashion to urethral cancer in the female. 4.9.5

Summary of evidence and recommendations for urethral diverticulum

Summary of evidence Magnetic resonance imaging has the best sensitivity and specificity for the diagnosis of urethral diverticula. Surgical removal of symptomatic urethral diverticula provides good long-term results; however, women should be counselled of the risk of recurrence and de novo SUI.

Recommendations Offer surgical removal of symptomatic urethral diverticula. If conservative treatment is adopted, warn patients of the small (1–6%) risk of cancer developing within the diverticulum. Carefully question and investigate patients for co-existing voiding dysfunction and urinary incontinence. Following appropriate counselling, address bothersome stress urinary incontinence at the time of urethral diverticulectomy with concomitant non-synthetic sling. Counsel patients regarding the possibility of de novo or persistent lower urinary tract symptoms including urinary incontinence despite technically successful urethral diverticulectomy.

LE 3 3

Strength rating Weak Weak Strong Weak Strong

5.

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Hammad, F.T. TVT can also cause urethral diverticulum. Int Urogynecol J Pelvic Floor Dysfunct, 2007. 18: 467. https://pubmed.ncbi.nlm.nih.gov/16821000 Mahdy, A., et al. Urethral diverticulum after tension-free vaginal tape procedure: case report. Urology, 2008. 72: 461 e5. https://pubmed.ncbi.nlm.nih.gov/18355901 Han, D.H., et al. Outcomes of surgery of female urethral diverticula classified using magnetic resonance imaging. Eur Urol, 2007. 51: 1664. https://pubmed.ncbi.nlm.nih.gov/17335961 Leach, G.E., et al. L N S C3: a proposed classification system for female urethral diverticula. Neurourol Urodyn, 1993. 12: 523. https://pubmed.ncbi.nlm.nih.gov/8312937 Cameron, A.P. Urethral diverticulum in the female: a meta-analysis of modern series. Minerva Ginecol, 2016. 68: 186. https://pubmed.ncbi.nlm.nih.gov/26545036 Blander, D.S., et al. Endoluminal magnetic resonance imaging in the evaluation of urethral diverticula in women. Urology, 2001. 57: 660. https://pubmed.ncbi.nlm.nih.gov/11306374 Pathi, S.D., et al. Utility of clinical parameters, cystourethroscopy, and magnetic resonance imaging in the preoperative diagnosis of urethral diverticula. Int Urogynecol J, 2013. 24: 319. https://pubmed.ncbi.nlm.nih.gov/22707007 Dwarkasing, R.S., et al. MRI evaluation of urethral diverticula and differential diagnosis in symptomatic women. AJR Am J Roentgenol, 2011. 197: 676. https://pubmed.ncbi.nlm.nih.gov/21862811 Chung, D.E., et al. Urethral diverticula in women: discrepancies between magnetic resonance imaging and surgical findings. J Urol, 2010. 183: 2265. https://pubmed.ncbi.nlm.nih.gov/20400161 Blander, D.S., et al. Images in clinical urology. Magnetic resonance imaging of a “saddle bag” urethral diverticulum. Urology, 1999. 53: 818. https://pubmed.ncbi.nlm.nih.gov/10197865 Khati, N.J., et al. MR imaging diagnosis of a urethral diverticulum. Radiographics, 1998. 18: 517. https://pubmed.ncbi.nlm.nih.gov/9536494 Rovner, E.S., et al. Diagnosis and reconstruction of the dorsal or circumferential urethral diverticulum. J Urol, 2003. 170: 82. https://pubmed.ncbi.nlm.nih.gov/12796650 Chou, C.P., et al. Imaging of female urethral diverticulum: an update. Radiographics, 2008. 28: 1917. https://pubmed.ncbi.nlm.nih.gov/19001648 Gugliotta, G., et al. Use of trans-labial ultrasound in the diagnosis of female urethral diverticula: A diagnostic option to be strongly considered. J Obstet Gynaecol Res, 2015. 41: 1108. https://pubmed.ncbi.nlm.nih.gov/25772163 Baradaran, N., et al. Female Urethral Diverticula in the Contemporary Era: Is the Classic Triad of the “3Ds” Still Relevant? Urology, 2016. 94: 53. https://pubmed.ncbi.nlm.nih.gov/27079128 Stav, K., et al. Urinary symptoms before and after female urethral diverticulectomy--can we predict de novo stress urinary incontinence? J Urol, 2008. 180: 2088. https://pubmed.ncbi.nlm.nih.gov/18804229 Ockrim, J.L., et al. A tertiary experience of urethral diverticulectomy: diagnosis, imaging and surgical outcomes. BJU Int, 2009. 103: 1550. https://pubmed.ncbi.nlm.nih.gov/19191783 Bhatia, N.N., et al. Urethral pressure profiles of women with urethral diverticula. Obstet Gynecol, 1981. 58: 375. https://pubmed.ncbi.nlm.nih.gov/7196559 Reid, R.E., et al. Role of urodynamics in management of urethral diverticulum in females. Urology, 1986. 28: 342. https://pubmed.ncbi.nlm.nih.gov/3094219 Summitt, R.L., Jr., et al. Urethral diverticula: evaluation by urethral pressure profilometry, cystourethroscopy, and the voiding cystourethrogram. Obstet Gynecol, 1992. 80: 695. https://pubmed.ncbi.nlm.nih.gov/1407897

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767.

768.

769.

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771. 772. 773.

774.

775.

776.

777.

778.

779.

780.

781.

782.

783. 784.

785.

786.

787.

Bass, J.S., et al. Surgical treatment of concomitant urethral diverticulum and stress incontinence. Urol Clin North Am, 1991. 18: 365. https://pubmed.ncbi.nlm.nih.gov/1902010 Ganabathi, K., et al. Experience with the management of urethral diverticulum in 63 women. J Urol, 1994. 152: 1445. https://pubmed.ncbi.nlm.nih.gov/7933181 Wagner, U., et al. [Significance of the urethral pressure profile in the diagnosis of urethral diverticulum]. Geburtshilfe Frauenheilkd, 1986. 46: 456. https://pubmed.ncbi.nlm.nih.gov/3093308 Thomas, A.A., et al. Urethral diverticula in 90 female patients: a study with emphasis on neoplastic alterations. J Urol, 2008. 180: 2463. https://pubmed.ncbi.nlm.nih.gov/18930487 Greiman, A.K., et al. Urethral diverticulum: A systematic review. Arab J Urol, 2019. 17: 49. https://pubmed.ncbi.nlm.nih.gov/31258943 Moran, P.A., et al. Urethral diverticula in pregnancy. Aust N Z J Obstet Gynaecol, 1998. 38: 102. https://pubmed.ncbi.nlm.nih.gov/9521406 Chang, Y.L., et al. Presentation of female urethral diverticulum is usually not typical. Urol Int, 2008. 80: 41. https://pubmed.ncbi.nlm.nih.gov/18204232 Ljungqvist, L., et al. Female urethral diverticulum: 26-year followup of a large series. J Urol, 2007. 177: 219. https://pubmed.ncbi.nlm.nih.gov/17162049 Enemchukwu, E., et al. Autologous Pubovaginal Sling for the Treatment of Concomitant Female Urethral Diverticula and Stress Urinary Incontinence. Urology, 2015. 85: 1300. https://pubmed.ncbi.nlm.nih.gov/26099875 Faerber, G.J. Urethral diverticulectomy and pubovaginal sling for simultaneous treatment of urethral diverticulum and intrinsic sphincter deficiency. Tech Urol, 1998. 4: 192. https://pubmed.ncbi.nlm.nih.gov/9892000 Romanzi, L.J., et al. Urethral diverticulum in women: diverse presentations resulting in diagnostic delay and mismanagement. J Urol, 2000. 164: 428. https://pubmed.ncbi.nlm.nih.gov/10893602 Swierzewski, S.J., 3rd, et al. Pubovaginal sling for treatment of female stress urinary incontinence complicated by urethral diverticulum. J Urol, 1993. 149: 1012. https://pubmed.ncbi.nlm.nih.gov/8483202 Dmochowski, R.R., et al. Update of AUA guideline on the surgical management of female stress urinary incontinence. J Urol, 2010. 183: 1906. https://pubmed.ncbi.nlm.nih.gov/20303102 Nickles, S.W., et al. Simple vs complex urethral diverticulum: presentation and outcomes. Urology, 2014. 84: 1516. https://pubmed.ncbi.nlm.nih.gov/25432847 Bodner-Adler, B., et al. Surgical management of urethral diverticula in women: a systematic review. Int Urogynecol J, 2016. 27: 993. https://pubmed.ncbi.nlm.nih.gov/26564222 Ingber, M.S., et al. Surgically corrected urethral diverticula: long-term voiding dysfunction and reoperation rates. Urology, 2011. 77: 65. https://pubmed.ncbi.nlm.nih.gov/20800882 Rovner, E. Bladder and Female Urethral Diverticula. 2020. https://abdominalkey.com/bladder-and-female-urethral-diverticula/ Lee, U.J., et al. Rate of de novo stress urinary incontinence after urethal diverticulum repair. Urology, 2008. 71: 849. https://pubmed.ncbi.nlm.nih.gov/18355904 Laudano, M.A., et al. Pathologic Outcomes following Urethral Diverticulectomy in Women. Adv Urol, 2014. 2014: 861940. https://pubmed.ncbi.nlm.nih.gov/24860605 Tsivian, M., et al. Female urethral diverticulum: a pathological insight. Int Urogynecol J Pelvic Floor Dysfunct, 2009. 20: 957. https://pubmed.ncbi.nlm.nih.gov/19582385 Thomas, R.B., et al. Adenocarcinoma in a female urethral diverticulum. Aust N Z J Surg, 1991. 61: 869. https://pubmed.ncbi.nlm.nih.gov/1750825

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6.

CONFLICT OF INTEREST

All members of the Non-neurogenic Female LUTS Panel have provided disclosure statements of all relationships that they have that might be perceived as a potential source of a conflict of interest. This information is publically accessible through the European Association of Urology website: https://uroweb.org/ guideline/non-neurogenic-female-luts/. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

7.

CITATION INFORMATION

The format in which to cite the EAU Guidelines will vary depending on the style guide of the journal in which the citation appears. Accordingly, the number of authors or whether, for instance, to include the publisher, location, or an ISBN number may vary. The compilation of the complete Guidelines should be referenced as: EAU Guidelines. Edn. presented at the EAU Annual Congress Milan 2021. ISBN 978-94-92671-13-4 If a publisher and/or location is required, include: EAU Guidelines Office, Arnhem, The Netherlands. http://uroweb.org/guidelines/compilations-of-all-guidelines/ References to individual guidelines should be structured in the following way: Contributors’ names. Title of resource. Publication type. ISBN. Publisher and publisher location, year.

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EAU Guidelines on

Paediatric Urology C. Radmayr (Chair), G. Bogaert, H.S. Dogan, J.M. Nijman (Vice-chair), Y.F.H. Rawashdeh, M.S. Silay, R. Stein, S. Tekgül Guidelines Associates: L.A. ‘t Hoen, J. Quaedackers, N. Bhatt

© European Association of Urology 2021

TABLE OF CONTENTS

PAGE

1. INTRODUCTION 1.1 Aim 1.2 Panel composition 1.3 Available publications 1.4 Publication history 1.5 Summary of changes 1.5.1 New recommendations

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METHODS 2.1 Introduction 2.2 Peer review

3. THE GUIDELINE 3.1 Phimosis 3.1.1 Epidemiology, aetiology and pathophysiology 3.1.2 Classification systems 3.1.3 Diagnostic evaluation 3.1.4 Management 3.1.5 Complications 3.1.6 Follow-up 3.1.7 Summary of evidence and recommendations for the management of phimosis 3.2 Management of undescended testes 3.2.1 Background 3.2.2 Classification 3.2.2.1 Palpable testes 3.2.2.2 Non-palpable testes 3.2.3 Diagnostic evaluation 3.2.3.1 History 3.2.3.2 Physical examination 3.2.3.3 Imaging studies 3.2.4 Management 3.2.4.1 Medical therapy 3.2.4.1.1 Medical therapy for testicular descent 3.2.4.1.2 Medical therapy for fertility potential 3.2.4.2 Surgical therapy 3.2.4.2.1 Palpable testes 3.2.4.2.1.1 Inguinal orchidopexy 3.2.4.2.1.2 Scrotal orchidopexy 3.2.4.2.2 Non-palpable testes 3.2.4.2.3 Complications of surgical therapy 3.2.4.2.4 Surgical therapy for undescended testes after puberty 3.2.5 Undescended testes and fertility 3.2.6 Undescended testes and malignancy 3.2.7 Summary of evidence and recommendations for the management of undescended testes 3.3 Testicular Tumours in prepubertal boys 3.3.1 Introduction 3.3.2 Clinical presentation 3.3.3 Evaluation 20 3.3.4 Treatment/Management 3.3.5 Tumour entities in prepubertal boys 3.3.6 Follow-up 3.3.7 Congenital Adrenal Hyperplasia (CAH) 3.4 Hydrocele 3.4.1 Epidemiology, aetiology and pathophysiology 3.4.2 Diagnostic evaluation 3.4.3 Management 3.4.4 Summary of evidence and recommendations for the management of hydrocele

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3.5 Acute scrotum 3.5.1 Epidemiology, aetiology and pathophysiology 3.5.2 Diagnostic evaluation 3.5.3 Management 3.5.3.1 Epididymitis 3.5.3.2 Testicular torsion 3.5.3.3 Surgical treatment 3.5.4 Follow-up 3.5.4.1 Fertility 3.5.4.2 Subfertility 3.5.4.3 Androgen levels 3.5.4.4 Unanswered questions 3.6 Hypospadias 3.6.1 Epidemiology, aetiology and pathophysiology 3.6.1.1 Epidemiology 3.6.2 Risk factors 3.6.3 Classification systems 3.6.4 Diagnostic evaluation 3.6.5 Management 3.6.5.1 Indication for reconstruction and therapeutic objectives 3.6.5.2 Pre-operative hormonal treatment 3.6.5.3 Age at surgery 3.6.5.4 Penile curvature 3.6.5.5 Urethral reconstruction 3.6.5.6 Re-do hypospadias repairs 3.6.5.7 Penile reconstruction following formation of the neo-urethra 3.6.5.8 Urine drainage and wound dressing 3.6.5.9 Outcome 3.6.6 Follow-up 3.6.7 Summary of evidence and recommendations for the management of hypospadias 3.7 Congenital penile curvature 3.7.1 Epidemiology, aetiology and pathophysiology 3.7.2 Diagnostic evaluation 3.7.3 Management 3.7.4 Summary of evidence and recommendations for the management of congenital penile curvature 3.8 Varicocele in children and adolescents 3.8.1 Epidemiology, aetiology and pathophysiology 3.8.2 Classification systems 3.8.3 Diagnostic evaluation 3.8.4 Management 3.8.5 Summary of evidence and recommendations for the management of varicocele 3.9 Urinary tract infections in children 3.9.1 Epidemiology, aetiology and pathophysiology 3.9.2 Classification systems 3.9.2.1 Classification according to site 3.9.2.2 Classification according to severity 3.9.2.3 Classification according to episode first/persistent/recurrent/ breakthrough 3.9.2.4 Classification according to symptoms 3.9.2.5 Classification according to complicating factors 3.9.3 Diagnostic evaluation 3.9.3.1 Medical history 3.9.3.2 Clinical signs and symptoms 3.9.3.3 Physical examination 3.9.3.4 Urine sampling, analysis and culture 3.9.3.4.1 Urine sampling 3.9.3.4.2 Urinalysis 3.9.3.4.3 Urine culture

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3.9.3.5 Imaging 39 3.9.3.5.1 Ultrasound 39 3.9.3.5.2 Radionuclide scanning/MRI 40 3.9.3.5.3 Voiding cystourethrography / urosonography 40 3.9.4 Management 41 3.9.4.1 Administration route of antibacterial therapy 41 3.9.4.2 Duration of therapy 41 3.9.4.3 Antimicrobial agents 41 3.9.4.4 Preventative measures 42 3.9.4.4.1 Chemoprophylaxis 42 3.9.4.4.2 Dietary supplements 42 3.9.4.4.3 Preputium 42 3.9.4.4.4 Bladder and bowel dysfunction 42 3.9.4.5 Monitoring of UTI 43 3.9.5 Summary of evidence and recommendations for the management of UTI in children 43 3.10 Day-time lower urinary tract conditions 44 3.10.1 Terminology, classification, epidemiology and pathophysiology 44 3.10.1.1 Filling-phase (storage) dysfunctions 44 3.10.1.2 Voiding-phase (emptying) dysfunctions 44 3.10.2 Diagnostic evaluation 45 3.10.3 Management 45 3.10.3.1 Specific interventions 46 3.10.4 Summary of evidence and recommendations for the management of day-time lower urinary tract conditions 47 3.11 Monosymptomatic nocturnal enuresis - bedwetting 47 3.11.1 Epidemiology, aetiology and pathophysiology 47 3.11.2 Diagnostic evaluation 48 3.11.3 Management 48 3.11.3.1 Supportive treatment measures 48 3.11.3.2 Conservative “wait and see” approach 48 3.11.3.3 Nocturnal enuresis wetting alarm treatment 48 3.11.3.4 Medical therapy 49 3.11.4 Summary of evidence and recommendations for the management of monosymptomatic enuresis 50 3.12 Management of neurogenic bladder 50 3.12.1 Epidemiology, aetiology and pathophysiology 50 3.12.2 Classification systems 51 3.12.3 Diagnostic evaluation 51 3.12.3.1 History and clinical evaluation 51 3.12.3.2 Laboratory and urinalysis 51 3.12.3.3 Ultrasound 51 3.12.3.4 Urodynamic studies/videourodynamic 51 3.12.3.4.1 Preparation before urodynamic studies 52 3.12.3.4.2 Uroflowmetry 52 3.12.3.5 Urodynamic studies 52 3.12.3.6 Voiding cystourethrogram 52 3.12.3.7 Renal scan 52 3.12.4 Management 52 3.12.4.1 Early management with intermittent catheterisation 53 3.12.4.2 Medical therapy 53 3.12.4.3 Management of faecal incontinence 54 3.12.4.4 Urinary tract infection 54 3.12.4.4.1 Urinary tract infection and clean intermittent catherisation 55 3.12.4.5 Sexuality 55 3.12.4.6 Bladder augmentation 55 3.12.4.7 Bladder outlet procedures 56 3.12.4.8 Catheterisable cutaneous channel. 57 3.12.4.9 Continent and incontinent cutaneous urinary diversion 57 3.12.5 Follow-up 57

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3.12.6 Self-organisation of patients 3.12.7 Summary of evidence and recommendations for the management of neurogenic bladder 3.13 Dilatation of the upper urinary tract (UPJ and UVJ obstruction) 3.13.1 Epidemiology, aetiology and pathophysiology 3.13.2 Diagnostic evaluation 3.13.2.1 Antenatal ultrasound 3.13.2.2 Postnatal ultrasound 3.13.2.3 Voiding cystourethrogram 3.13.2.4 Diuretic renography 3.13.3 Management 3.13.3.1 Prenatal management 3.13.3.1.1 Antibiotic prophylaxis for antenatal hydronephrosis 3.13.3.2 UPJ obstruction 3.13.3.3 Megaureter 3.13.3.3.1 Non-operative management 3.13.3.3.2 Surgical management 3.13.4 Conclusion 3.13.5 Summary of evidence and recommendations for the management of UPJ-, UVJ-obstruction 3.14 Vesicoureteric reflux 3.14.1 Epidemiology, aetiology and pathophysiology 3.14.2 Diagnostic evaluation 3.14.2.1 Infants presenting with prenatally diagnosed hydronephrosis 3.14.2.2 Siblings and offspring of reflux patients 3.14.2.3 Recommendations for paediatric screening of VUR 3.14.2.4 Children with febrile urinary tract infections 3.14.2.5 Children with lower urinary tract symptoms and vesicoureteric reflux 3.14.3 Disease management 3.14.3.1 Non-surgical therapy 3.14.3.1.1 Follow-up 3.14.3.1.2 Continuous antibiotic prophylaxis 3.14.3.2 Surgical treatment 3.14.3.2.1 Subureteric injection of bulking materials 3.14.3.2.2 Open surgical techniques 3.14.3.2.3 Laparoscopy and robot-assisted 3.14.4 Summary of evidence and recommendations for the management of vesicoureteric reflux in childhood 3.15 Urinary stone disease 3.15.1 Epidemiology, aetiology and pathophysiology 3.15.2 Classification systems 3.15.2.1 Calcium stones 3.15.2.2 Uric acid stones 3.15.2.3 Cystine stones 3.15.2.4 Infection stones (struvite stones) 3.15.3 Diagnostic evaluation 3.15.3.1 Imaging 3.15.3.2 Metabolic evaluation 3.15.4 Management 3.15.4.1 Extracorporeal shockwave lithotripsy 3.15.4.2 Percutaneous nephrolithotomy 3.15.4.3 Ureterorenoscopy 3.15.4.4 Open or laparoscopic stone surgery 3.15.5 Summary of evidence and recommendations for the management of urinary stones 3.16 Obstructive pathology of renal duplication: ureterocele and ectopic ureter 3.16.1 Epidemiology, aetiology and pathophysiology 3.16.1.1 Ureterocele 3.16.1.2 Ectopic ureter 3.16.2 Classification systems

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3.16.2.1 Ureterocele 83 3.16.2.1.1 Ectopic (extravesical) ureterocele 83 3.16.2.1.2 Orthotopic (intravesical) ureterocele 83 3.16.2.2 Ectopic ureter 83 3.16.3 Diagnostic evaluation 84 3.16.3.1 Ureterocele 84 3.16.3.2 Ectopic ureter 84 3.16.4 Management 84 3.16.4.1 Ureterocele 84 3.16.4.1.1 Early treatment 84 3.16.4.1.2 Re-evaluation 85 3.16.4.2 Ectopic ureter 85 3.16.5 Summary of evidence and recommendations for the management of obstructive pathology of renal duplication: ureterocele and ectopic ureter 86 3.17 Disorders of sex development 86 3.17.1 Introduction 86 3.17.2 Current classification of DSD conditions 87 3.17.3 Diagnostic evaluation 88 3.17.3.1 The neonatal emergency 88 3.17.3.2 Family history and clinical examination 88 3.17.4 Gender assignment 89 3.17.5 Risk of tumour development 90 3.17.6 Recommendations for the management of disorders of sex development 90 3.18 Congenital lower urinary tract obstruction (CLUTO) 90 3.18.1 Posterior urethral valves 91 3.18.1.1 Epidemiology, aetiology and pathophysiology 91 3.18.2 Classification systems 91 3.18.2.1 Urethral valve 91 3.18.3 Diagnostic evaluation 91 3.18.4 Management 92 3.18.4.1 Antenatal treatment 92 3.18.4.2 Postnatal treatment 92 3.18.5 Follow-up 93 3.18.6 Summary 94 3.18.7 Summary of evidence and recommendations for the management of posterior urethral valves 96 3.19 Rare Conditions in Childhood 96 3.19.1 Urachal remnants 96 3.19.1.1 Introduction 96 3.19.1.2 Epidemiology 97 3.19.1.3 Symptoms 97 3.19.1.4 Diagnosis 97 3.19.1.5 Treatment 97 3.19.1.6 Pathology of removed remnants 98 3.19.1.7 Urachal cancer 98 3.19.1.8 Conclusion 98 3.19.1.9 Recommendation for management of urachal remnants 98 3.19.2 Papillary tumours of the bladder in children and adolescents (Papillary urothelial neoplasm of low malignant potential or transitional cell carcinoma) 99 3.19.2.1 Incidence 99 3.19.2.2 Differences and similarities of papillary tumours of the bladder in children and adults 99 3.19.2.3 Risk factors 99 3.19.2.4 Presentation 99 3.19.2.5 Investigations and treatment 99 3.19.2.6 Histology 99 3.19.2.7 Additional treatment 99 3.19.3 Penile rare conditions 100 3.19.3.1 Cystic lesions 100 3.19.3.2 Vascular malformations 101

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3.19.3.3 Neurogenic lesions 3.19.3.4 Soft tissue tumours of penis 3.19.3.5 Penile Lymphedema 3.20 Paediatric urological trauma 3.20.1 Paediatric renal trauma 3.20.1.1 Epidemiology, aetiology and pathophysiology 3.20.1.2 Classification systems 3.20.1.3 Diagnostic evaluation 3.20.1.3.1 Haematuria 3.20.1.3.2 Blood pressure 3.20.1.3.3 Choice of imaging method 3.20.1.4 Disease management 3.20.1.5 Recommendations for the diagnosis and management of paediatric renal trauma 3.20.2 Paediatric ureteral trauma 3.20.2.1 Diagnostic evaluation 3.20.2.2 Management 3.20.2.3 Recommendations for the diagnosis and management of paediatric ureteral trauma 3.20.3 Paediatric bladder injuries 3.20.3.1 Diagnostic evaluation 3.20.3.2 Management 3.20.3.2.1 Intraperitoneal injuries 3.20.3.2.2 Extraperitoneal injuries 3.20.3.3 Recommendations for the diagnosis and management of paediatric bladder injuries 3.20.4 Paediatric urethral injuries 3.20.4.1 Diagnostic evaluation 3.20.4.2 Disease management 3.20.4.3 Recommendations for the diagnosis and management of paediatric trauma 3.21 Peri-operative fluid management 3.21.1 Epidemiology, aetiology and pathophysiology 3.21.2 Disease management 3.21.2.1 Pre-operative fasting 3.21.2.2 Maintenance therapy and intra-operative fluid therapy 3.21.2.3 Peri-operative feeding and fluid management 3.21.3 Summary of evidence and recommendations for the management of peri-operative fluid management 3.22 Post-operative pain management: general information 3.22.1 Epidemiology, aetiology and pathophysiology 3.22.2 Diagnostic evaluation 3.22.3 Disease management 3.22.3.1 Drugs and route of administration 3.22.3.2 Circumcision 3.22.3.2.1 Penile, inguinal and scrotal surgery 3.22.3.3 Bladder and kidney surgery 3.22.4 Summary of evidence and recommendations for the management of post-operative pain 3.23 Basic principles of laparoscopic surgery in children 3.23.1 Epidemiology, aetiology and pathophysiology 3.23.2 Technical considerations and physiological consequences 3.23.2.1 Pre-operative evaluation 3.23.2.2 Abdominal insufflation 3.23.2.3 Pulmonary effects 3.23.2.4 Cardiovascular effects 3.23.2.5 Effects on renal function 3.23.2.6 Effects on neurological system 3.23.3 Summary of evidence and recommendations for laparoscopy in children

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CONFLICT OF INTEREST

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CITATION INFORMATION

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1.

INTRODUCTION

1.1

Aim

The European Association of Urology (EAU) Paediatric Urology Guidelines Panel has prepared these Guidelines with the aim of increasing the quality of care for children with urological conditions. This Guideline document is limited to a number of common clinical pathologies in paediatric urological practice, as covering the entire field of paediatric urology in a single guideline document is unattainable. The majority of urological clinical problems in children are specialised and in many ways differ to those in adults. This publication intends to outline a practical and preliminary approach to paediatric urological conditions. Complex and rare conditions that require special care with experienced doctors should be referred to designated centres where paediatric urology practice has been fully established and a multidisciplinary team is available. Over time, paediatric urology has developed and matured, establishing its diverse body of knowledge and expertise and may now be ready to distinguish itself from its parent specialties. Thus, paediatric urology has recently emerged in many European countries as a distinct subspecialty of both urology and paediatric surgery and presents a unique challenge in the sense that it covers a large area with many different schools of thought and a huge diversity in management. Knowledge gained by increasing experience, new technological advances and non-invasive diagnostic screening modalities has had a profound influence on treatment modalities in paediatric urology, a trend that is likely to continue in the years to come. It must be emphasised that clinical guidelines present the best evidence available to the experts but following guideline recommendations will not necessarily result in the best outcome. Guidelines can never replace clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions - also taking personal values and preferences/individual circumstances of children and their caregivers into account. Guidelines are not mandates and do not purport to be a legal standard of care.

1.2

Panel composition

The EAU Paediatric Urology Guidelines Panel consists of an international group of clinicians with particular expertise in this area. All experts involved in the production of this document have submitted potential conflict of interest statements, which can be viewed on the EAU Website: http://uroweb.org/guideline/ paediatric-urology/.

1.3

Available publications

A quick reference document (Pocket guidelines) is available, both in print and as an app for iOS and Android devices. These are abridged versions which may require consultation together with the full text version. A number of translated versions, alongside several scientific publications are also available [1-7]. All documents can be viewed through the EAU website: http://uroweb.org/guideline/paediatric-urology/.

1.4

Publication history

The Paediatric Urology Guidelines were first published in 2001 [8]. This 2021 publication includes a number of updated chapters and sections as detailed below.

1.5

Summary of changes

The literature for the complete document has been assessed and updated, wherever relevant. Key changes in the 2021 publication: • • • • • • • • • •

Section 3.2 - Management of undescended testes: Both the literature and the text have been updated; Section 3.3 - Testicular Tumours in prepubertal boys: This is a new section in the Guideline; Section 3.5 - Acute Scrotum: Both the literature and the text have been updated; Section 3.6 - Hypospadias: Both the literature and the text have been updated; Section 3.7 - Congenital penile curvature: Both the literature and the text have been updated; Section 3.9 - Urinary Tract Infections: Both the literature and the text have been extensively updated; Section 3.10 - Day-time lower urinary tract conditions: The literature has been updated resulting in minor amendments to the text; Section 3.13 - Dilatation of the upper urinary tract (UPJ and UVJ obstruction): The literature has been updated resulting in minor amendments to the text: Section 3.15 - Urinary stone disease: The literature has been updated resulting in minor amendments to the text; Section 3.18 - Congenital lower urinary tract obstruction (CLUTO): Both the literature and the text have been updated;

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•

Section 3.19 – Rare Conditions - This is a new section in the Guideline comprising of urachal remnants, papillary tumours of the bladder and penile rare conditions.

1.5.1

New recommendations 3.3

Recommendations for testicular tumours in prepubertal boys

Recommendations High-resolution ultrasound (7.5 – 12.5 MHz), preferably a doppler ultrasound, should be performed to confirm the diagnosis. Alpha-fetoprotein (AFP) should be determined in prepubertal boys with a testicular tumour before surgery. Surgical exploration should be done with the option for frozen section, but not as an emergency operation. Organ-preserving surgery should be performed in all benign tumours. Staging (MRI abdomen /CT chest) should only be performed in patients with a malignant tumour to exclude metastases. MRI should only be performed in patients with the potential malignant Leydig or Sertoli-cell-tumours to rule out lymph node enlargement. Patients with a non-organ confined tumour should be referred to paediatric oncologists post-operatively. 3.19

Recommendations for rare conditions in children

3.19.1

Urachal remnants

LE 3

Strength rating Strong

2b

Strong

3

Strong

3 3

Strong Strong

4

Weak

4

Weak

Recommendations Urachal remnants with no epithelial tissue carry little risk of malignant transformation. Asymptomatic and non-specific atretic urachal remnants can safely be managed nonoperatively. Urachal remnants (UR) incidentally identified during diagnostic imaging for non-specific symptoms should also be observed non-operatively since they tend to resolve spontaneously. A small urachal remnant, especially at birth, may be viewed as physiological. Urachal remnants in patients younger than 6 months are likely to resolve with non-operative management. Follow-up is necessary only when symptomatic for 6 to 12 months. Surgical excision of urachal remnants solely as a preventive measure against later malignancy appears to have minimal support in the literature. Only symptomatic URs should be safely removed by open or laparoscopic approach. A voiding cystourethrogram is only recommended when presenting with febrile UTIs. 3.19.2

Strong

Strong Strong Strong Strong Strong Strong

Papillary tumours of the bladder

Recommendations Ultrasound is the first investigation of choice for the diagnosis of paediatric bladder tumours. Cystoscopy should be reserved if a bladder tumour is suspected on imaging for diagnosis and treatment. After histological confirmation, inflammatory myofibroblastic bladder tumours should be resected locally. Follow-up should be every 3-6 months in the first year, and thereafter at least annually with urinanalysis and an ultrasound for at least 5 years.

10

Strength rating Strong Strong

LE 3

Strength rating Strong

3

Strong

4

Weak

4

Weak

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3.19.3

Penile conditions

Recommendations Treatment of penile cystic lesions is by total surgical excision, it is mainly indicated for cosmetic or symptomatic (e.g. infection) reasons. Propranolol is currently first line treatment for infantile haemangiomas. Conservative management is the first-line treatment for penile lymphedema. In symptomatic cases or in patients with functional impairment, surgical intervention may become necessary for penile lymphedema.

2.

METHODS

2.1

Introduction

LE 4

Strength rating Weak

2b 4 4

Strong Weak Weak

These Guidelines were compiled based on current literature following a structured review. Databases covered by the searches included Pubmed, Ovid, EMBASE and the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews. Application of a structured analysis of the literature was not possible in many conditions due to a lack of well-designed studies. The limited availability of large randomised controlled trials (RCTs) - influenced also by the fact that a considerable number of treatment options relate to surgical interventions on a large spectrum of different congenital problems - means this document is largely a consensus document. Clearly there is a need for continuous re-evaluation of the information presented in this document. For each recommendation within the guidelines there is an accompanying online strength rating form, the basis of which is a modified GRADE methodology [9, 10]. Each strength rating form addresses a number of key elements namely: 1. the overall quality of the evidence which exists for the recommendation, references used in this text are graded according to a classification system modified from the Oxford Centre for Evidence-Based Medicine Levels of Evidence [11]; 2. the magnitude of the effect (individual or combined effects); 3. the certainty of the results (precision, consistency, heterogeneity and other statistical or study related factors); 4. the balance between desirable and undesirable outcomes; 5. the impact of patient values and preferences on the intervention; 6. the certainty of those patient values and preferences. These key elements are the basis which panels use to define the strength rating of each recommendation. The strength of each recommendation is represented by the words ‘strong’ or ‘weak’ [12]. The strength of each recommendation is determined by the balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including certainty of estimates), and nature and variability of patient values and preferences. The strength rating forms will be available online. Additional information can be found in the general Methodology section of this print, and online at the EAU websit; http://www.uroweb.org/guideline/. A list of Associations endorsing the EAU Guidelines can also be viewed online at the above address.

2.2

Peer review

All chapters of the Paediatric Urology Guidelines were peer-reviewed in 2015.

3.

THE GUIDELINE

3.1

Phimosis

This chapter does not deal with neonatal circumcision as practised in the USA, nor mass circumcision as practised in many African countries as part of a national program to prevent HIV. Also “religious and cultural” circumcision is not discussed. At present in some European countries professional organisations do not

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support circumcision for these reasons and it is no longer covered by insurance in these countries. Special centres have been set up, where well-trained doctors perform circumcisions under sedation and local anaesthetics at a lower cost. In all circumstances facilities have to comply with national regulations regarding hygiene, special equipment, pain protocols and follow-up. Usually these clinics have an agreement with a nearby hospital for the immediate treatment of possible complications. It is estimated that 37-39% of men worldwide are circumcised [13]. 3.1.1 Epidemiology, aetiology and pathophysiology At the end of the first year of life, retraction of the foreskin behind the glandular sulcus is possible in approximately 50% of boys; this increases to approximately 89% by the age of three years. The incidence of phimosis is 8% in six to seven year olds and in just 1% in males aged sixteen to eighteen years [14]. 3.1.2 Classification systems Phimosis is either primary with no sign of scarring, or secondary (pathological) to a scarring such as balanitis xerotica obliterans (BXO) [14]. Balanitis xerotica obliterans, also termed lichen sclerosis, has been recently found in 35% of circumcised prepuce in children and adolescents and in 17% of boys younger than ten years presenting with phimosis. The clinical appearance of BXO in children may be confusing and does not always correlate with the final histopathological results. Lymphocyte-mediated chronic inflammatory disease was the most common finding [15, 16] (LE: 2b). Phimosis has to be distinguished from normal agglutination (adhesion) of the foreskin to the glans, which is a more or less lasting physiological phenomenon with clearly-visible meatus and partial retraction [17]. Separation of the prepuce from the glans is based on accumulated epithelial debris (smegma) and penile erections. Forceful preputial retraction should be discouraged to avoid cicatrix formation [18]. Paraphimosis must be regarded as an emergency situation: retraction of a too narrow prepuce behind the glans penis into the glanular sulcus may constrict the shaft and lead to oedema of the glans and retracted foreskin. It interferes with perfusion distally from the constrictive ring and brings a risk of preputial necrosis. 3.1.3 Diagnostic evaluation The diagnosis of phimosis and paraphimosis is made by physical examination. If the prepuce is not retractable, or only partly retractable, and shows a constrictive ring on drawing back over the glans penis, a disproportion between the width of the foreskin and the diameter of the glans penis has to be assumed. In addition to the constricted foreskin, there may be adhesions between the inner surface of the prepuce and the glanular epithelium and/or a fraenulum breve. Paraphimosis is characterised by a retracted foreskin with the constrictive ring localised at the level of the sulcus, which prevents replacement of the foreskin over the glans. 3.1.4 Management Conservative treatment is an option for primary phimosis. The class 4 therapies were more effective over placebo and manual stretching [19]. A corticoid ointment or cream (0.05-0.1%) can be administered twice a day over a period of 4-8 weeks with a success rate of > 80% [20-23] (LE: 1b). A recurrence rate of up to 17% can be expected [24]. This treatment has no side effects and the mean bloodcortisol levels are not significantly different from an untreated group of patients [25] (LE: 1b). The hypothalamic pituitary-adrenal axis was not influenced by local corticoid treatment [26]. Adhesion of the foreskin to the glans does not respond to steroid treatment [20] (LE: 2). Operative treatment of phimosis in children is dependent on the caregivers’ preferences and can be plastic or radical circumcision after completion of the second year of life. Alternatively, the Shang Ring may be used especially in developing countries [27]. Plastic circumcision has the objective of achieving a wide foreskin circumference with full retractability, while the foreskin is preserved (dorsal incision, partial circumcision, trident preputial plasty, combining 2 Z-plasties and a Y plasty) [28, 29]. However, this procedure carries the potential for recurrence of the phimosis [30]. In the same session, adhesions are released and an associated fraenulum breve is corrected by fraenulotomy. Meatoplasty is added if necessary. In all cases meticulous haemostasis is mandatory and absorbable interrupted sutures are most often used. An absolute indication for circumcision is secondary phimosis. In primary phimosis (including those not responding to medical treatment), recurrent balanoposthitis and recurrent urinary tract infections (UTIs) in patients with urinary tract abnormalities are indications for surgical intervention [31-34] (LE: 2b). Male circumcision significantly reduces the bacterial colonisation of the glans penis with regard to both non-uropathogenic and uropathogenic bacteria [35] (LE: 2b). Simple ballooning of the foreskin during micturition is not a strict indication for circumcision. Routine neonatal circumcision to prevent penile carcinoma is not indicated. A meta-analysis could not find any risk in uncircumcised patients without a history of phimosis [36]. Contraindications for circumcision

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are: an acute local infection and congenital anomalies of the penis, particularly hypospadias or buried penis, as the foreskin may be required for a reconstructive procedure [37, 38]. Circumcision can be performed in children with coagulopathy with 1-5% suffering complications (bleeding), if haemostatic agents or a diathermic blade are used [39, 40]. Childhood circumcision has an appreciable morbidity and should not be recommended without a medical reason and also taking into account epidemiological and social aspects [41-45] (LE: 1b). Balanitis xerotica obliterans is associated with meatal pathology (stenosis) after circumcision in up to 20% of boys and adjuvant local steroid treatment is advised [16, 46]. Treatment of paraphimosis consists of manual compression of the oedematous tissue with a subsequent attempt to retract the tightened foreskin over the glans penis. Injection of hyaluronidase beneath the narrow band or 20% mannitol may be helpful to release the foreskin [47, 48] (LE: 3-4). If this manoeuvre fails, a dorsal incision of the constrictive ring is required. Depending on the local findings, a circumcision is carried out immediately or can be performed in a second session. 3.1.5 Complications Complications following circumcision vary and have been reported between 0-30% [45]. In a recent study Hung et al. found during a 5-year follow-up period 2.9% complications in non-neonates of which 2.2% were early (within 30 days after circumcision). Non-healing wounds, haemorrhage, wound infection, meatal stenosis, redundant skin and non-satisfying cosmetic appearance as well as cicatrix formation and trapped penis all may occur [49]. 3.1.6 Follow-up Any surgery done on the prepuce requires an early follow-up of four to six weeks after surgery. 3.1.7

Summary of evidence and recommendations for the management of phimosis

Summary of evidence Treatment for phimosis usually starts after two years of age or according to caregivers’ preference. In primary phimosis, conservative treatment with a third generation corticoid ointment or cream is a first-line treatment with a success rate of more than 80%.

Recommendations Offer corticoid ointment or cream to treat primary symptomatic phimosis. Circumcision will also solve the problem. Treat primary phimosis in patients with recurrent urinary tract infection and/or with urinary tract abnormalities. Circumcise in case of lichen sclerosus or scarred phimosis. Treat paraphimosis by manual reposition and proceed to surgery if it fails. Avoid retraction of asymptomatic preputial adhesions.

3.2

LE 3 1b

LE 1b 2b 2b

Strength rating Strong Strong Strong

2b 3 2b

Strong Strong Weak

Management of undescended testes

3.2.1 Background Cryptorchidism or undescended testis is one of the most common congenital malformations of male neonates. Incidence varies and depends on gestational age, affecting 1.0-4.6% of full-term and 1.1-45% of preterm neonates. Following spontaneous descent within the first months of life, nearly 1.0% of all full-term male infants still have undescended testes at one year of age [50]. This congenital malformation may affect both sides in up to 30% of cases [51]. In newborn cases with non-palpable or undescended testes on both sides and any sign of disorders of sex development (DSDs) like concomitant hypospadias, urgent endocrinological and genetic evaluation is required [52]. 3.2.2 Classification The term cryptorchidism is most often used synonymously for undescended testes. The most useful classification of undescended testes is distinguishing into palpable and non-palpable testes, and clinical management is decided by the location and presence of the testes (see Figure 1). Approximately 80% of all undescended testes are palpable [53]. Acquired undescended testes can be caused by entrapment after herniorrhaphy or spontaneously referred to as ascending testis. Palpable testes include true undescended testes and ectopic testes. Non-palpable testes include intra-abdominal, inguinal, absent, and sometimes also some ectopic testes. Most importantly, the diagnosis of palpable or non-palpable testis needs to be confirmed once the child is under general anaesthesia, as this is the first step of any surgical procedure for undescended testes.

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Figure 1: Classification of undescended testes

Undescended testis

Palpable

Inguinal

Non-palpable

Inguinal

Ectopic

Intraabdominal

Absent

Ectopic

Agenesis

Retractile

Vanishing testis

3.2.2.1 Palpable testes Undescended testes A true undescended testis is on its normal path of descent but is halted on its way down to the scrotum. Depending on the location, the testes may be palpable or not, as in the case of testes arrested in the inguinal canal. Ectopic testes If the position of a testis is outside its normal path of descent and outside the scrotum, the testis is considered to be ectopic. The most common aberrant position is in the superficial inguinal pouch. Sometimes an ectopic testis can be identified in a femoral, perineal, pubic, penile or even contralateral position. Usually, there is no possibility for an ectopic testis to descend spontaneously to the correct position; therefore, it requires surgical intervention. In addition, an ectopic testis might not be palpable due to its position. Retractile testes Retractile testes have completed their descent into a proper scrotal position but can be found again in a suprascrotal position along the path of their normal descent. This is due to an overactive cremasteric reflex [54]. Retractile testes can be easily manipulated down to the scrotum and remain there at least temporarily. They are typically normal in size and consistency. However, they may not be normal and should be monitored carefully since up to one-third can ascend and become undescended [55]. 3.2.2.2 Non-palpable testes Among the 20% of non-palpable testes, 50-60% are intra-abdominal, canalicular or peeping (right inside the internal inguinal ring). The remaining 20% are absent and 30% are atrophic or rudimentary. Intra-abdominal testes Intra-abdominal testes can be located in different positions, with most of them being found close to the internal inguinal ring. However, possible locations include the kidney, anterior abdominal wall, and retrovesical space. In the case of an open internal inguinal ring, the testis may be peeping into the inguinal canal.

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Absent testes Monorchidism can be identified in up to 4% of boys with undescended testes, and anorchidism (bilateral absence) in < 1%. Possible pathogenic mechanisms include testicular agenesis and atrophy after intrauterine torsion with the latter one most probably due to an in utero infarction of a normal testis by gonadal vessel torsion. The term “vanishing testis” is commonly used for this condition [56]. 3.2.3 Diagnostic evaluation History taking and physical examination are key in evaluating boys with undescended testes. Localisation studies using different imaging modalities are usually without any additional benefit. 3.2.3.1 History Caregivers should be asked for maternal and paternal risk factors, including hormonal exposure and genetic or hormonal disorders. If the child has a history of previously descended testes this might be suggestive of testicular ascent [57]. Prior inguinal surgery is indicative of secondary undescended testes due to entrapment. 3.2.3.2 Physical examination An undescended testis is pursued by carefully advancing the examining fingers along the inguinal canal towards the pubis region, perhaps with the help of lubricant. A possible inguinal testis can be felt to bounce under the fingers [58]. A non-palpable testis in the supine position may become palpable once the child is in a sitting or squatting position. If no testis can be identified along the normal path of descent, possible ectopic locations must be considered. In the event of unilateral non-palpable testis, the contralateral testis needs to be examined. Its size and location can have important prognostic implications. Any compensatory hypertrophy suggests testicular absence or atrophy [59]. Nevertheless, this does not preclude surgical exploration since the sign of compensatory hypertrophy is not specific enough [60, 61]. In the event of bilateral undescended testes and any evidence or sign of DSDs, such as genital ambiguity, or scrotal hyperpigmentation, further evaluation including endocrinological and genetic assessment becomes mandatory [62]. 3.2.3.3 Imaging studies Imaging studies cannot determine with certainty that a testis is present or not [63]. Ultrasound (US) lacks the diagnostic sensitivity to detect the testis confidently or establish the absence of an intra-abdominal testis [64]. Consequently, the use of different imaging modalities, such as US or Magnetic resonance imaging (MRI) [65], for undescended testes is limited and only recommended in specific and selected clinical scenarios (e.g. identification of Müllerian structures in cases with suspicion of DSDs) [64]. 3.2.4 Management Treatment should be started at the age of six months. After that age, undescended testes rarely descend [66]. Any kind of treatment leading to a scrotally positioned testis should be finished by twelve months, or eighteen months at the latest, because histological examination of undescended testes at that age has already revealed a progressive loss of germ cells and Leydig cells [67]. The early timing of treatment is also driven by the final adult results on spermatogenesis and hormone production, as well as on the risk of tumour development [68]. 3.2.4.1 Medical therapy Unfortunately, most of the studies on hormonal treatment have been of poor quality, with heterogeneous and mixed patient populations, testis location, schedules and dosages of hormonal administration. Additionally, long-term data are almost completely lacking. Short-term side effects of hormonal treatment include increased scrotal erythema and pigmentation, and induction of pubic hair and penile growth. Some boys experience pain after intramuscular injection of human chorionic gonadotropin (hCG). All of these tend to regress after treatment cessation [69, 70]. 3.2.4.1.1 Medical therapy for testicular descent Hormonal therapy using hCG or gonadotropin-releasing hormone (GnRH) is based on the hormonal dependence of testicular descent, but has a limited success rate of only 20% [71]. However, it must be taken into account that almost 20% of these descended testes have the risk of re-ascending later [72]. In general, success rates depend on testicular location. The higher the testis is located prior to therapy, the lower the success rate, suggesting that testicular position is an important determinant of success [69]. Some authors recommend combined hCG-GnRH treatment. Unfortunately, it is poorly documented and the treatment groups were diverse. Some studies reported successful descent in up to 38% of non-responders to monotherapy [73]. The Panel consensus is that endocrine treatment to achieve testicular descent is not recommended (LE: 4).

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Human chorionic gonadotropin Human chorionic gonadotropin (hCG) stimulates endogenous testosterone production and is administered by intramuscular injection. Several dose and administration schedules are reported. There is no proven difference between 1.5 IU and weight-based doses up to 3.0 IU every other day for fourteen days [74]. Similar response rates were achieved with 500 IU once weekly and 1.50 IU three times weekly [75]. However, there is evidence that dosing frequency might affect testicular descent rates. Fewer lower dose injections per week for five weeks seem to be superior to one higher dose every seven to ten days for three weeks with regard to testicular descent [76]. Gonadotropin-releasing hormone Gonadotropin-releasing hormone (GnRH) analogues (e.g., buserelin and gonadorelin) are available as nasal sprays, thus avoiding painful intramuscular injections. A typical dosage regimen consists of 1.2 mg per day in three divided doses, for four weeks. Success rates are wide ranging, from 9 to 60%, due to multiple treatment strategies and heterogeneous patient populations [77]. 3.2.4.1.2 Medical therapy for fertility potential Hormonal treatment may improve fertility indices [77, 78] and therefore serve as an additional tool to orchidopexy. There is no difference in treatment with GnRH before (neo-adjuvant) or after (adjuvant) surgical orchidolysis and orchidopexy in terms of increasing fertility index, which may be a predictor for fertility later in life [79]. It is still unknown whether this effect on testicular histology persists into adulthood but it has been shown that men who were treated in childhood with buserelin had better semen analyses compared with men who had childhood orchidopexy alone or placebo treatment [77]. It is reported that hCG treatment may be harmful to future spermatogenesis through increased apoptosis of germ cells, including acute inflammatory changes in the testes and reduced testicular volume in adulthood [80]. Identification of specific subgroups of boys with undescended testes who would benefit from such an approach using hormones is difficult. Since these important data on specific groups as well as additional support on the long-term effects are still lacking, the Nordic consensus does not recommend hormonal therapy [81]. The consensus of the Panel is to recommend endocrine treatment with GnRH analogues in a dosage described above for boys with bilateral undescended testes to preserve the fertility potential (LE: 4). 3.2.4.2 Surgical therapy If a testis has not concluded its descent at the age of six months (corrected for gestational age), and since spontaneous testicular descent is unlikely to occur after that age, surgery should be performed within the subsequent year, and by age eighteen months at the latest [68]. In addition, early orchidopexy can be followed by partial catch-up testicular growth, which is not the case in delayed surgery [79]. All these findings recommend performing early orchidopexy between the ages of six and twelve months [66]. But despite early and successful orchiopexy within the first year of life up to 25% of boys with nonsyndromic undescended testes may be at risk for infertility based on hormonal and histological data, as a recently published series on 333 boys showed. This is especially true for bilateral cases, but in addition in about 5% of unilateral cases reduced numbers of germ cells were detected in testicular biopsies as well [82]. 3.2.4.2.1 Palpable testes Surgery for palpable testes includes orchidofunicolysis and orchidopexy, either via an inguinal or scrotal approach. The latter approach is mainly reserved for low-positioned, undescended testes, with the pros and cons of each method being weighed against each other [83]. 3.2.4.2.1.1 Inguinal orchidopexy Inguinal orchidopexy is a widely used technique with a high success rate of up to 92% [84]. Important steps include mobilisation of the testis and spermatic cord to the level of the internal inguinal ring, with dissection and division of all cremasteric fibres, to prevent secondary retraction and detachment of the gubernaculum testis. The patent processus vaginalis needs to be ligated proximally at the level of the internal ring, because an unidentified or inadequately repaired patent processus vaginalis is an important factor leading to failure of orchidopexy [85]. Any additional pathology has to be taken care of, such as removal of an appendix testis (hydatid of Morgagni). At this moment the size of the testis can be measured and the connection of the epididimis to the testis can be judged and described in the protocol. Some boys have a significant dissociation between testis and epididymis which is prognostically bad for fertility. Finally, the mobilised testicle needs to be placed in a sub-dartos pouch within the hemi-scrotum without any tension. If the length achieved using the above-mentioned technique is still inadequate, the Prentiss manoeuvre, which consists of dividing the inferior epigastric vessels and transposing the spermatic cord medially, in order to provide a straight course to the

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scrotum, might be an option [86]. With regard to fixation sutures, if required, they should be made between the tunica vaginalis and the dartos musculature [87]. Lymph drainage of a testis that has undergone surgery for orchidopexy may have changed from high retroperitoneal drainage to iliac and inguinal drainage, which might become important in the event of later malignancy [88]. 3.2.4.2.1.2 Scrotal orchidopexy Low-positioned, palpable undescended testis can be fixed through a scrotal incision including division of the gubernaculum, and the processus vaginalis needs to be probed to check for patency [89]. Otherwise, fixation in the scrotum is carried out correspondingly to the inguinal approach. In up to 20% of cases, an inguinal incision will be compulsory to correct an associated inguinal hernia [90]. Any testicular or epididymal appendages can be easily identified and removed. A systematic review shows that the overall success rates ranged from 88 to 100%, with rates of recurrence and post-operative testicular atrophy or hypotrophy < 1% [83]. Another recently published systematic review and meta-analysis revealed similar outcome data regarding post-operative complications, including wound infection, testicular atrophy, testicular reascent, and hernia for palpable low positioned undescended testes. The only siginificant difference was the shorter operative time [91]. 3.2.4.2.2 Non-palpable testes For non-palpable testes, surgery must clearly determine whether a testis is present or not [92]. If a testis is found, the decision has to be made to remove it or bring it down to the scrotum. An important step in surgery is a thorough re-examination once the boy is under general anaesthesia, since a previously non-palpable testis might be identifiable and subsequently change the surgical approach to standard inguinal orchidopexy, as described above. Otherwise, the easiest and most accurate way to locate an intra-abdominal testis is diagnostic laparoscopy [93]. Subsequent removal or orchidolysis and orchidopexy can be carried out using the same approach to achieve the therapeutic aims [94]. Some tend to start with inguinal surgical exploration, with possible laparoscopy during the procedure [95]. If an ipsilateral scrotal nubbin is suspected, and contralateral compensatory testicular hypertrophy is present, a scrotal incision with removal of the nubbin, thus confirming the vanishing testis, is an option avoiding the need for laparoscopy [96]. During laparoscopy for non-palpable testes, possible anatomical findings include spermatic vessels entering the inguinal canal (40%), an intra-abdominal (40%) or peeping (10%) testis, or blind-ending spermatic vessels confirming vanishing testis (10%) [97]. If there is a vanishing testis, the procedure is finished once blind-ending spermatic vessels are clearly identified. If the vessels enter the inguinal canal, an atrophic testis may be found upon inguinal exploration or a healthy testis that needs to undergo standard orchidopexy [98]. A peeping testis can be placed down in the scrotum laparoscopically or via an inguinal incision [99]. Placement of an intra-abdominal testis can sometimes be a surgical challenge. Usually, testes lying > 2 cm above the internal inguinal ring may not reach the scrotum without division of the testicular vessels [100]. Under such circumstances, a FowlerStephens orchidopexy may be an option [101] (see Figure 2). Proximal cutting and transection of the testicular vessels, with conservation of the collateral arterial blood supply, via the deferential artery and cremasteric vessels comprise the key features of the Fowler-Stephens procedure. Recently, a modification with low spermatic vessel ligation has gained popularity, allowing blood supply from the testicular artery to the deferential artery. An additional advantage is the position of the peritoneal incision, leading to a longer structure, to ease later scrotal placement [102]. Due to the nature of these approaches the testis is at risk of hypotrophy or atrophy if the collateral blood supply is insufficient [103]. The testicular survival rate in the one-stage Fowler-Stephens technique varies between 50 and 65% based on post-operative Doppler-ultrasound findings [104]. For two-stage procedures success rates increase up to 90% [105]. The advantages of two-stage orchidopexy, with the second part done usually six months after the first, are to allow for development of collateral blood supply and to create greater testicular mobility [106]. In addition, preservation of the gubernaculum may also decrease the chance of testicular atrophy [107]. An alternative might be microsurgical auto-transplantation, which has a success rate of up to 90%. However, this approach requires skilled and experienced surgeons and is performed in a limited number of centres [108]. 3.2.4.2.3 Complications of surgical therapy Surgical complications are usually uncommon, with testicular atrophy being the most serious. A systematic review revealed an overall atrophy rate for primary orchidopexy of 1.83%, 28.1% for one-stage FowlerStephens procedure, and 8.2% for the two-stage approach [109]. Other rare complications comprise testicular ascent and vas deferens injury besides local wound infection, dehiscence, and haematoma. 3.2.4.2.4 Surgical therapy for undescended testes after puberty A study on 51 men diagnosed with inguinal unilateral undescended testis and a normal contralateral one, with

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no history of any previous therapy, demonstrated a wide range of changes upon histological evaluation. Nearly half of the study population still had significant germ cell activity at different maturation levels. Importantly, the incidence of intratubular germ cell neoplasia was 2% [110]. The Panel consensus recommends orchiectomy in post-pubertal boys with an undescended testis and a normal contralateral one in a scrotal position. Figure 2: Treatment of unilateral non-palpable undescended testes Unilateral non-palpable testis

Re-exam under anaesthesia

Still non-palpable

Diagnostic laparoscopy

Inguinal exploration with possible laparoscopy

Palpable

Standard orchidopexy

Testis close to internal ring

Testis too high for orchidopexy

Blind ending spermatic vessels

Spermatic vessels enter inguinal ring

Laparoscopic or inguinal orchidopexy

Staged FowlerStephens procedure

Vanishing testis no further steps

Inguinal exploration

3.2.5 Undescended testes and fertility The association of undescended testes with compromised fertility [111] is extensively discussed in the literature and seems to be a result of multiple factors, including germ cell loss, impaired germ cell maturation [112], Leydig cell diminution and testicular fibrosis [113]. Although boys with one undescended testis have a lower fertility rate, they have the same paternity rate as those with bilateral descended testes. Boys with bilateral undescended testes suffer both lower fertility and paternity rates. Fertility rate is the number of offspring born per mating pair, individual or population, whereas paternity reflects the actual potential of fatherhood [114]. The age at which surgical intervention for an undescended testis occurs seems to be an important predictive factor for fertility later in life. Endocrinological studies revealed higher inhibin-B and lower follicle-stimulating hormone (FSH) levels in men who underwent orchidopexy at two years of age compared to individuals who had surgery later, which is indicative of a benefit of earlier orchidopexy [115]. In addition, others demonstrated a relation between undescended testes and increased loss of germ cells and Leydig cells, which is also suggestive of prompt orchidopexy being a significant factor for fertility preservation [116]. Outcome studies for untreated bilateral undescended testes revealed that 100% are oligospermic and 75% azoospermic. Among those successfully treated for bilateral undescended testes, 75% still remain oligospermic and 42% azoospermic [113]. In summary, early surgical correction of undescended testes is highly recommended before twelve months of age, and by eighteen months at the latest for preservation of fertility potential [67].

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3.2.6 Undescended testes and malignancy Boys who are treated for an undescended testis have an increased risk of developing testicular malignancy. Screening and self-examination both during and after puberty is therefore recommended [117]. A Swedish study, with a cohort of almost 17,000 men (56 developed a testicular tumour) who were treated surgically for undescended testes and followed for 210,000 person-years, showed that management of undescended testes before the onset of puberty decreased the risk of testicular cancer. The relative risk of testicular cancer among those who underwent orchidopexy before thirteen years of age was 2.2 compared to the Swedish general population; this increased to 5.4 for those treated after thirteen years of age [118]. A systematic review and meta-analysis of the literature have also concluded that pre-pubertal orchidopexy may reduce the risk of testicular cancer and that early surgical intervention is indicated in boys with undescended testes [119]. 3.2.7

Summary of evidence and recommendations for the management of undescended testes

Summary of evidence An undescended testis justifies treatment early in life to avoid loss of spermatogenic potential. A failed or delayed orchidopexy may increase the risk of testicular malignancy later in life. The earlier the treatment, the lower the risk of impaired fertility and testicular cancer. In unilateral undescended testis, fertility rate is reduced whereas paternity rate is not. In bilateral undescended testes, fertility and paternity rates are impaired. The treatment of choice for undescended testis is surgical replacement in the scrotum. The palpable testis is usually treated surgically using an inguinal approach. The non-palpable testis is most commonly approached laparoscopically. There is no consensus on the use of hormonal treatment. Recommendations Do not offer medical or surgical treatment for retractile testes instead undertake close follow-up on a yearly basis until puberty. Perform surgical orchidolysis and orchidopexy before the age of twelve months, and by eighteen months at the latest. Evaluate male neonates with bilateral non-palpable testes for possible disorders of sex development. Perform a diagnostic laparoscopy to locate an intra-abdominal testicle. Hormonal therapy in unilateral undescended testes is of no benefit for future paternity. Offer endocrine treatment in case of bilateral undescended testes. Inform the patient/caregivers about the increased risk of a later malignancy with an undescended testis in a post-pubertal boy or older and discuss removal in case of a contralateral normal testis in a scrotal position.

3.3

LE 2a 2a 2a 1b 1b 1b 2b 2b 2b

LE 2a

Strength rating Strong

2b

Strong

1b

Strong

1a 2a

Strong Strong

4 3

Weak Weak

Testicular Tumours in prepubertal boys

3.3.1 Introduction Testicular tumours account for approximately 1-2% of all paediatric solid tumours. [120]. Testicular tumours in prepubertal boys differ in several aspects to testicular tumours in adolescent and adult men: they have a lower incidence, they have a different histologic distribution (teratomas and yolk sac tumours are more common and germ cell tumours are less common) and they are more often benign. A recent epidemiological study showed that in children under the age of 15 years the incidence is highest in Asia (4.2 per million) and South America (5 per million) and lowest in Europe (2.1 per million) and North America (2.5 per million). This is in contrast to the incidence in adolescent and young adults where the highest incidence is in Europe (137.4 per million), and North America (94.9 per million), while a lower incidence was observed in South and Central America (66.5 per million) and Asia (27.1 per million) [121]. For age distribution in prepubertal boys, there is a small peak around the age of two years [122]. Some recent studies demonstrated that up to 60-75% of the tumours are benign [120, 123-127]. Intratubular neoplasia (TIN) is practically non-existent in children [128-131]. Testicular tumours can generally be classified as germ cell or stromal tumours. One specific tumour type is the gonadoblastoma, which contains germ cell and stromal cell tumour types and will occur almost exclusively in the setting of disorders of sexual differentiation [132].

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In the past 30 years, it has clearly been shown, that there is a fundamental difference between testicular tumours in childhood and those in adulthood - not only in terms of the difference and incidence [121] but also in terms of histology [128]. In prepubertal boys, most intratesticular tumours are benign, whereas post puberty the tumours are most likely malignant. 3.3.2 Clinical presentation Clinical presentation is a painless scrotal mass in more than 90% of the patients, detected by the caregiver, physician or the patient himself. A history of a trauma, pain or hernia is rare. A hydrocele can be found in 15 – 50% [124, 133]. In boys with early onset of puberty (e.g. early penile and prepubic hair growth) as well as high testosterone and low gonadotropin levels, a Leydig cell tumour should be excluded [134]. In patients presenting with a scrotal mass, paratesticular tumours should also be taken into account as a differential diagnosis. However, these are even less common compared to intratesticular tumours. The spectrum of paratesticular tumours includes benign tumours such as leiomyoma, fibroma, lipoma, haemangioma, cystic lymphangioma and lipoblastoma as well as malignant tumours such as the paratesticular rhabdomyosarcoma with an excellent prognosis and the rare melanotic neuroectodermal tumour of infancy with a high recurrence rate [135-138]. As most of them are benign, intra-operative frozen section should be available during surgery. An organ sparing surgical approach is preferred in benign tumours, whereas in malignant tumour standard orchiectomy is carried out. 3.3.3 Evaluation To confirm the diagnosis, a high-resolution ultrasound (US) examination (7.5 – 12.5 MHz), preferably a doppler ultrasound, is required. The detection rate is almost 100% [139-142]. With high-resolution US, microlithiasis - small hyperdense areas without sound shadows - is increasingly seen in prepubertal boys. A recent meta-analysis showed that only 4 out of 296 boys (< 19 years of age diagnosed with microlithiasis) developed a testicular tumour of whom two previously had a testicular tumour on the opposite or ipsilateral site [143]. If microlithiasis shows up in patients with additional risk factors for testicular tumour, then the caregivers/ patients should be informed about the increased risk and encouraged to carry out regular self-examinations similar to patients treated for undescended testis [144]. There is no evidence, that regular sonographic followup is useful [143]. The risk for infertility may be higher in patients with microlithiasis and if these patients have any sign of infertility later, the risk of developing a tumour seems to be higher compared to patients without microlithiasis and infertility [145]. Due to the low incidence of a contralateral tumour, even in cases of testicular microlithiasis, there is no indication for contralateral testicular biopsy in prepubertal boys. Age should be taken into account, when tumour markers are used. Human chorionic gonadotropin (ß-hCG) is derived from chorion carcinoma, embryonal carcinoma or seminoma. However, these tumours are extremely rare in prepubertal boys and therefore ß-hCG is not useful in prepubertal boys. Alpha-fetoprotein (AFP) has a clear limitation of its sensitivity and specificity in the first months of life [133] and sometimes takes up to 12 months before the serum concentration reaches the known standard values (< 10 ng/mL) [127, 146]. It is produced by > 90% of yolk sac tumours. Teratomas can also produce AFP, but not to that extent of yolk sac tumours [147]. Alpha-fetoprotein should be measured before any therapeutic intervention (tumour enucleation/ orchiectomy) and ideally should be available at the time of the procedure. Alpha-fetoprotein has a serum biological half-life of 5 days and should be measured 5 days after tumour resection/orchiectomy in those with an elevated AFP. There is no urgent need for pre-operative staging, as this has no consequence before the definitive histology is available. 3.3.4 Treatment/Management If a testicular tumour is suspected, surgery with the option of intra-operative frozen section should be performed. It is not necessary to do this as an emergency procedure. However, in order to confirm the diagnosis and to avoid familial anxiety, the operation should be scheduled as soon as possible, preferably within the next few days. Organ-preserving surgery should be performed, whenever possible. A recent published review article showed that out of 227 patients with organ-sparing surgery only two cases (one in a patient with an epidermoid cyst and one in a patient with a mature teratoma) had a recurrence [148-150]. Orchiectomy could be considered only if normal testicular parenchyma is no longer detectable in the preoperatively high-resolution ultrasound and/or the AFP is > 100 ng/mL in a > 12-month-old boy: highly suspicious of a yolk sac tumour. For surgical technique, the Panel is in favour of an inguinal approach. Furthermore, clamping of the vessels has the advantage of a better view, when organ sparing surgery is performed. However, there is no evidence in the literature, that tumour-spread is prevented by clamping the vessels. Whenever possible, testis sparing surgery 20

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should be performed along with frozen sections during surgery to confirm the diagnosis (begin vs. malignant tumour) and to confirm if a microscopically margin-negative resection is performed, in which no gross or microscopic tumour remains in the primary tumour bed (R0 resection). In cases of an R0 resection, the tunica is closed and the testis is replaced in the scrotum. In case of R1 resection (removal of all macroscopic disease, but microscopic margins are positive for tumour) confirmed by frozen section in a malignant or potential malignant tumour, an orchiectomy should be performed at the same time of surgery. If the final pathology later demonstrates a R1 resection in a malignant tumour despite intra-operative negative margins on frozen section, an inguinal orchiectomy can safely be performed. In patients with a malignant tumour (yolk sac tumour, immature teratoma) staging should be performed including an MRI of the abdomen and a CT-scan from the chest. If there is any suspicion of a non-organ confined tumour, the patient should be referred to a paediatric oncologist. In patients with the rare diagnosis of a Granulosa cell tumour, imaging of the abdomen to exclude enlarged lymph nodes is reasonable as this may be a potentially malignant tumour; in those with Sertoli or a Leydig cell tumour, an MRI is recommended, as 10% are malignant and the metastases do not respond very well to chemotherapy or radiation in the adult literature [151, 152]. The TNM classification from 2015 for adult testicular tumours can be used in patients with a malignant tumour [153]. In benign tumours (mature teratoma, epidermoid cysts) no further staging is required. 3.3.5 Tumour entities in prepubertal boys Teratomas are usually benign in prepubertal children and represent the greatest proportion of intratesticular tumours (around 40%) [120, 154]. They present at a median age of 13 months (0-18 months). Only in adolescent and adults, they should be considered as malignant tumours. Histologically they can consist of a combination of the three primitive embryological germ-cell layers (ectoderm, mesoderm and endoderm). Most of these elements shows microscopically mature elements [155]; however, some immature teratomas in this age group have also been reported [156]. To exclude any malignant potential, like focal areas of a yolk-sac tumour, the entire specimen should be investigated. On US examination a heterogenous picture with some calcification is seen [157] and AFP should be less than 100 ng/mL in an infant. After organ-sparing surgery only one recurrence was reported in the literature [150]. Epidermoid cysts are of ectodermal origin and seem to be related to well-differentiated teratomas; they are always benign [155]. Keratin-producing epithelium is responsible for the keratinised-squamous-epithelial deposits, which appear hyperechogenic in an US [157]. Organ-sparing surgery should be performed and if confirmed by histology, there is no need for surveillance despite the fact that one “recurrence” has been reported 13 years after diagnosis [149]. Juvenile granulosa cell tumours occur usually in the first year of life, typically within the first 6 months [158]. They are well circumscribed and have a typical yellow-tan appearance; 2/3 have cystic elements, 1/3 solid [158]. The stroma can be fibrous or fibromyxoid. So far, no recurrence has been reported after organ-sparing surgery [158, 159]. Leydig cell tumours arising from the testosterone producing Leydig cells should be suspected in boys with early onset of puberty with high testosterone and low gonadotropin levels [134]. Patients are usually between 5 and 10 years of age; the tumours are well circumscribed with yellow-brown nodules. In children there are no reports of malignant Leydig cell tumours and after organ sparing surgery, there are no reported recurrences to date [160, 161]. In the adult literature, there is a malignancy rate of 10% reported and primary retroperitoneal lymphadenectomy should be discussed in cases with enlarged lymph nodes, as these metastases do not respond very well to chemotherapy or radiation [162]. Around 1/5 of the Sertoli-cell tumours occur in children; usually within the first year of life [163]. In the paediatric age group, the large-cell calcifying Sertoli cell tumours (LCCSCT) are the most common tumour variant [164, 165]. They can occur in patients with complex dysplastic syndromes, such as the Carney or Peutz-Jeghers syndrome [165-167]. Except one case report with the histological diagnosis of a malignant LCCSCT [164], all other reported tumours are benign, therefore organ-sparing surgery should be performed. Yolk sac tumours are the predominant prepubertal malignant germ cell tumours and may represent around 15% of the prepubertal tumours in boys [120]. They also have a number of other names: endodermal sinus tumours, juvenile embryonal carcinoma, clear cell carcinoma, orchioblastoma, vitellineum, archenteronoma and sometimes extraembryonal mesoblastoma [168]. They are histologically mostly solid, yellow-grey tumours. They occur usually within the first two years of life [169]. Up to 80-85% of the tumours are organ confined (Stage I) [170]. The tumour usually spreads haematogenously (chest). Twenty percent of those with Stage I disease may develop visible metastasis in 20% within the next 2 years. In a German study, 14 out of 91 patients with Stage I had a recurrence after observation – all were cured by chemotherapy alone. Four out of PAEDIATRIC UROLOGY - LIMITED UPDATE MARCH 2021

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five with metastatic disease initially, were cured by chemotherapy after radical orchiectomy [171]. In a recent published series from China, 21 out of 90 paediatric patients with a Stage I yolk sac tumour received primary chemotherapy. One of the 21 had a recurrence, whereas 29 out of 69 who underwent surveillance after initial orchiectomy had a recurrence. The overall 4-year survival rate was 97.8% [169], almost the same recurrence rate has also been reported by American oncology groups [172, 173]. Therefore in patients with Stage I disease (no metastatic disease in the MRI-abdomen and CT scan of the chest as well as normal age-adapted AFPvalues) close follow-up together with the paediatric oncologists including AFP every 2-3 months and MRI of the abdomen is recommended, at least for the first 2-3 years [133]. This is especially recommended in those with invasions of the lymphatic vessels, as this has been shown to be a prognostic factor in one of the recent series [169]. In cases of recurrence, chemotherapy should be performed by paediatric oncologists according to national study protocols. 3.3.6 Follow-up Regular US examination is recommended in the follow-up period to detect any recurrence and/or other abnormalities. As there are only a few studies with recurrence after testicular sparing surgery or orchiectomy, no clear recommendation can be made concerning the interval and the duration of follow-up. However, doing an US examination every 3-6 months within the first year seems reasonable, as few recurrences have been detected at this time and the rate of atrophy is extremely low after organ-sparing surgery [148]. Only in patients with a malignant tumour, regular follow-up examination after the first year of surgery seems reasonable (see above). The follow-up in patients with a Leydig cell tumour should include endocrinological examinations. Using the SEER data base, the 5-year relative survival for testicular malignancies for patients < 14 years of age diagnosed with localised testicular cancer was 97.4%, and for those with distant disease 72.6% [174]. 3.3.7 Congenital Adrenal Hyperplasia Boys with a congenital adrenal hyperplasia (CAH) represent a special group. Up to a third of the patients have so-called testicular adrenal rest tumours (TARTs) This proportion increase with age [175, 176]. It is most likely to be ectopic adrenal cells, which are growing under pathological stimulation from Adrenocorticotropic Hormone (ACTH) [177]. They have no malignant potential, but they can have a lasting impact on fertility by displacing the normal testicular parenchyma [177, 178]. These patients should be offered US screening and advice on fertility with the option of cryopreservation [178]. As far as is known, no malignant tumour has been described in patients with a typical TART. As a result, the indication for surgical intervention in these patients to rule out a malignant tumour should be offered very cautiously. Summary of evidence Testicular tumours in prepubertal boys have a lower incidence and a different histologic distribution compared to the adolescent and adult patients. In prepupertal boys up to 60-75% of testicular tumours are benign.

Recommendations High-resolution ultrasound (7.5 – 12.5 MHz), preferably a doppler ultrasound, should be performed to confirm the diagnosis. Alpha-fetoprotein should be determined in prepubertal boys with a testicular tumour before surgery. Surgical exploration should be done with the option for frozen section, but not as an emergency operation. Organ-preserving surgery should be performed in all benign tumours. Staging (MRI abdomen/CT chest) should only be performed in patients with a malignant tumour to exclude metastases. Magnetic resonance imaging should only be performed in patients with the potential malignant Leydig or Sertoli-cell-tumours to rule out lymph node enlargement. Patients with a non-organ confined tumour should be referred to paediatric oncologists post-operatively.

3.4

LE 2a 3

LE 3

Strength rating Strong

2b

Strong

3

Strong

3 3

Strong Strong

4

Weak

4

Weak

Hydrocele

3.4.1 Epidemiology, aetiology and pathophysiology Hydrocele is defined as a collection of fluid between the parietal and visceral layers of the tunica vaginalis [179]. Pathogenesis of primary hydrocele is based on patency of the processus vaginalis in contrast with secondary hydrocele. Incomplete obliteration of the processus vaginalis peritonei results in formation of various types of

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communicating hydrocele; a large open processus vaginalis allowing passage of abdominal viscera results in clinical hernia [180]. The exact time of spontaneous closure of the processus vaginalis is not known. It persists in approximately 80-94% of newborns and in 20% of adults [181]. If complete obliteration of the processus vaginalis occurs with patency of mid-portion, a hydrocele of the cord occurs. Scrotal hydroceles without associated patency of the processus vaginalis are also encountered in newborns [182]. Non-communicating hydroceles, based on an imbalance between the secretion and re-absorption of this fluid, are found secondary to minor trauma, testicular torsion, epididymitis, varicocele operation (due to ligation of the lymphatics) or may appear as a recurrence after primary repair of a communicating or non-communicating hydrocele. 3.4.2 Diagnostic evaluation The classic description of a communicating hydrocele is that of a hydrocele that fluctuates in size, and is usually related to ambulation. It may be diagnosed by history-taking and physical investigation. Transillumination of the scrotum provides the diagnosis in the majority of cases, keeping in mind that fluid filled intestine and some pre-pubertal tumours may transilluminate as well [183, 184]. If the diagnosis is that of a hydrocele, there will be no history of reducibility and no associated symptoms; the swelling is translucent, smooth and usually not tender. If there are any doubts about the character of an intrascrotal mass, scrotal US should be performed and has nearly 100% sensitivity in detecting intrascrotal lesions. Doppler US studies help to distinguish hydroceles from varicocele and testicular torsion, although these conditions may also be accompanied by a hydrocele. 3.4.3 Management In the majority of infants, surgical treatment of hydrocele is not indicated within the first twelve months because of the tendency for spontaneous resolution [185] (LE: 2). Little risk is taken by initial observation as progression to hernia is rare and does not result in incarceration [185]. Early surgery is indicated if there is suspicion of a concomitant inguinal hernia or underlying testicular pathology [186, 187] (LE: 2). Persistence of a simple scrotal hydrocele beyond twelve months of age may be an indication for surgical correction. There is no evidence that this type of hydrocele risks testicular damage. The natural history of hydrocele is poorly documented beyond the age of two years and according to a systematic review there is no good evidence to support current practice. Delaying surgery may reduce the number of procedures necessary without increasing morbidity [188]. The question of contralateral disease should be addressed by both history-taking and physical examination at the time of initial consultation [189] (LE: 2). In late-onset hydrocele, suggestive of a noncommunicating hydrocele, there is a reasonable chance of spontaneous resolution (75%) and expectant management of six to nine months is recommended [190]. In the paediatric age group, the operation consists of ligation of the patent processus vaginalis or scrotal via inguinal incision and the distal stump is left open, whereas in hydrocele of the cord the cystic mass is excised or unroofed [184, 186, 191, 192] (LE: 4). In expert hands, the incidence of testicular damage during hydrocele or inguinal hernia repair is very low (0.3%) (LE: 3). Laparoscopic hernia repair with percutaneous ligation of the patent processes vaginalis is a minimally invasive alternative to open inguinal herniorrhaphy [193, 194]. Sclerosing agents should not be used because of the risk of chemical peritonitis in communicating processus vaginalis peritonei [184, 186] (LE: 4). The scrotal approach (Lord or Jaboulay technique) is used in the treatment of a secondary non-communicating hydrocele. 3.4.4

Summary of evidence and recommendations for the management of hydrocele

Summary of evidence LE In the majority of infants, surgical treatment of hydrocele is not indicated within the first twelve months 2a due to the tendency for spontaneous resolution. Little risk is taken by initial observation as progression to hernia is rare. In the paediatric age group, an operation would generally involve ligation of the patent processus 4 vaginalis via inguinal incision.

Recommendations In the majority of infants, observe hydrocele for twelve months prior to considering surgical treatment. Perform early surgery if there is suspicion of a concomitant inguinal hernia or underlying testicular pathology. Perform a scrotal ultrasound in case of doubt about the character of an intrascrotal mass. Do not use sclerosing agents because of the risk for chemical peritonitis.

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LE 2a

Strength rating Strong

2b

Strong

4

Strong

4

Strong

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3.5

Acute scrotum

3.5.1 Epidemiology, aetiology and pathophysiology Acute scrotum is a paediatric urological emergency, most commonly caused by torsion of the testis or appendix testis, or epididymitis/epididymo-orchitis [195-200]. Other causes of acute scrotal pain are idiopathic scrotal oedema, mumps orchitis, varicocele, scrotal haematoma, incarcerated hernia, appendicitis or systemic disease (e.g. Henoch-Schönlein purpura) [201-213]. Trauma can also be a cause of acute scrotum due to posttraumatic haematomas, testicular contusion, rupture, dislocation or torsion [214-219]. Scrotal fat necrosis has also been reported to be an uncommon cause of mild-to-moderate scrotal pain in pre-pubertal overweight boys after exposure to cold [220]. In this chapter testicular torsion and epididymitis are discussed, while recurrent epididymitis is discussed in the chapter dealing with infections. Torsion of the testis occurs most often in the neonatal period and around puberty, whereas torsion of the appendix testis occurs over a wider age range [221]. Epididymitis affects two age groups: less than one year and twelve to fifteen years [222, 223]. One study predicted the annual incidence of epididymitis around 1.2 per 1,000 children [224]. Perinatal torsion of the testis most often occurs prenatally. Bilateral torsion comprises 11-21% of all perinatal cases [225]. Most cases of perinatal torsion are extravaginal, in contrast to the usual intravaginal torsion which occurs during puberty. 3.5.2 Diagnostic evaluation Patients usually present with scrotal pain, except in neonatal torsion. The sudden onset of invalidating pain in combination with vomiting is typical for torsion of the testis or appendix testis [226, 227]. In general, the duration of symptoms at presentation is shorter in testicular torsion (69% present within twelve hours) and torsion of the appendix testis (62%) compared to epididymitis (31%) [197, 198, 223]. Prepubertal males are more likely to present with atypical symptoms and delayed presentation and diagnosis, leading to delayed surgical intervention and a higher rate of orchiectomy, compared to postpubertal boys [228]. In the early phase, location of the pain can lead to diagnosis. Patients with acute epididymitis experience a tender epididymis, whereas patients with testicular torsion are more likely to have a tender testicle, in case of torsion of the appendix testis there may be isolated tenderness of the superior pole of the testis [223]. An abnormal (horizontal) position of the testis is more frequent in testicular torsion than epididymitis [197]. Looking for absence of the cremasteric reflex is a simple method with 100% sensitivity and 66% specificity for testicular torsion [222, 227] (LE: 3). Elevation of the scrotum may reduce complaints in epididymitis, but not in testicular torsion. Fever occurs more often in epididymitis (11-19%). The classical sign of a “blue dot” was found only in 10-23% of patients with torsion of the appendix testis [196, 197, 222, 229]. In many cases, it is not easy to determine the cause of acute scrotum based on history and physical examination alone [195-200, 222, 229]. A positive urine culture is only found in a few patients with epididymitis [199, 222, 229, 230]. It should be remembered that a normal urinalysis does not exclude epididymitis. Similarly, an abnormal urinalysis does not exclude testicular torsion. Doppler US is useful to evaluate acute scrotum, with 63.6-100% sensitivity and 97-100% specificity, a positive predictive value of 100% and negative predictive value of 97.5% [231-236] (LE: 3). The use of Doppler US may reduce the number of patients with acute scrotum undergoing scrotal exploration, but it is operator-dependent and can be difficult to perform in pre-pubertal patients [233, 237]. It may also show a misleading arterial flow in the early phases of torsion and in partial or intermittent torsion. Of key importance, persistent arterial flow does not exclude testicular torsion. In a multicentre study of 208 boys with torsion of the testis, 24% had normal or increased testicular vascularisation [233]. A comparison with the other side should always be done. Better results were reported using high-resolution US (HRUS) for direct visualisation of the spermatic cord twist with a sensitivity of 97.3% and specificity of 99% [233, 238] (LE: 2). A so-called positive whirlpool sign (the presence of a spiral-like pattern), has a pooled sensitivity and specificity of 0.73 (95% CI, 0.65-0.79) and 0.99 (95% CI, 0.92-0.99), respectively, and may be viewed as a definitive sign for testicular torsion. But its role in neonates is limited [239]. Scintigraphy and, more recently, dynamic contrast-enhanced subtraction MRI of the scrotum also provide a comparable sensitivity and specificity to US [240-243]. These investigations may be used when diagnosis is less likely and if torsion of the testis still cannot be excluded from history and physical examination. This should be done without inordinate delays for emergency intervention [229]. The diagnosis of acute epididymitis in boys is mainly based on clinical judgement and adjunctive investigation. However, it should be remembered that findings of secondary inflammatory changes in the absence of evidence of an extra-testicular nodule by Doppler US might suggest an erroneous diagnosis of

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epididymitis in children with torsion of the appendix testes [244]. Pre-pubertal boys with acute epididymitis have an incidence of underlying urogenital anomalies of 25-27.6%. Complete urological evaluation in all children with acute epididymitis is still debatable [199, 222, 224]. 3.5.3 Management 3.5.3.1 Epididymitis In pre-pubertal boys, the aetiology is usually unclear, with an underlying pathology in about 25%. A urine culture is usually negative, and unlike in older boys, a sexually transmitted disease is very rare. Antibiotic treatment, although often started, is not indicated in most cases unless urinalysis and urine culture show a bacterial infection [224, 245]. Epididymitis is usually self-limiting and with supportive therapy (i.e. minimal physical activity and analgesics) heals without any sequelae (LE: 3). However, bacterial epididymitis can be complicated by abscess or necrotic testis and surgical exploration is required [246]. 3.5.3.2 Testicular torsion Manual detorsion of the testis is done without anaesthesia, and should be attempted in all patients if possible, because it is associated with improved surgical salvage rates [247]. It should initially be done by outward rotation of the testis - like opening a book -, unless the pain increases or if there is obvious resistance. Success is defined as the immediate relief of all symptoms and normal findings at physical examination [248] (LE: 3;). Doppler US may be used for guidance [249]. Bilateral orchiopexy is still required after successful detorsion. This should not be done as an elective procedure, but rather immediately following detorsion. One study reported residual torsion during exploration in 17 out of 53 patients, including eleven patients who had reported pain relief after manual detorsion [248, 250]. External cooling before exploration may be effective in reducing ischaemia reperfusion injury and preserving the viability of the torsed and the contralateral testis [251]. Medical treatments aimed at limiting such injury remain experimental [252-255]. Torsion of the appendix testis can be managed non-operatively with the use of anti-inflammatory analgesics (LE: 4). During the six-week follow-up, clinically and with US, no testicular atrophy was revealed. Surgical exploration is done in equivocal cases and in patients with persistent pain [236]. Although metachronous torsion of the appendix testis may occur in up to 8.5%, it is not necessary to explore the contralateral side, given the benign nature ot the problem. Besides it has been demonstrated that the NNT is 24 [256]. 3.5.3.3 Surgical treatment Testicular torsion is an urgent condition which requires prompt surgical treatment. The two most important determinants of early salvage rate of the testis are the time between onset of symptoms and detorsion, and the degree of cord twisting [257]. Severe testicular atrophy occurred after torsion for as little as four hours when the turn was > 360°. In cases of incomplete torsion (180-360°), with symptom duration up to twelve hours, no atrophy was observed. However, a necrotic or severely atrophied testis was found in all cases of torsion > 360° and symptom duration > 24 hours [258]. Early surgical intervention with detorsion (mean torsion time less than thirteen hours) was found to preserve fertility [259]. Urgent surgical exploration is mandatory in all cases of testicular torsion within 24 hours of symptom onset. In patients with testicular torsion > 24 hours, exploration may be performed as a semi-elective exploration procedure [257, 258] (LE: 3), unless there is a clear history of torsion-detorsion in which urgent exploration should still be considered. In case of prolonged torsion (> 24 hours) it is still subject to debate whether the surgically detorsed testis should be preserved. An alternative to detorsion and fixation may be to perform orchiectomy. A study found that sperm quality was preserved after both orchiectomy and orchidopexy in comparison to normal control men, although orchiectomy resulted in better sperm morphology [260]. Incision of the tunica albuginea with tunica vaginalis graft to prevent or treat compartment syndrome has also been suggested [261]. In neonates with signs of testicular torsion at birth the duration of symptoms will not be clear. The decision to perform surgical exploration should be weighed against the general condition of the child. In this age group the operation can safely be done under spinal anesthesia. New onset of symptoms of testicular torsion in neonates should be considered a surgical emergency similar to older boys. During exploration, fixation of the contralateral testis is also performed. It is good clinical practice to also perform fixation of the contralateral testis in prenatal and neonatal torsion, although there is no literature to support this, and to remove an atrophied testicle [262]. Recurrence after orchidopexy is rare (4.5%) and may occur several years later. There is no consensus recommendation about the preferred type of fixation and suture material [260, 261, 264].

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3.5.4 Follow-up Patients require follow-up mainly for fertility issues and hormonal consequences. Despite timely and adequate detorsion and fixation of the testicle, up to half of the patients may develop testicular atrophy, even when intraoperatively assessed as viable, and should be counselled accordingly [264, 265]. 3.5.4.1 Fertility The results vary and are conflicting. In one study, unilateral torsion of the testis seriously intervened with subsequent spermatogenesis in about 50% of the patients and produced borderline impairment in another 20% [242]. Although, 30% of affected testicles with mumps orchitis show a degree of atrophy, long-term outcome in terms of fertility is not conclusive [266]. A recent study showed a normal pregnancy rate after unilateral testicular torsion, with no difference between the patients undergoing orchidopexy and those after orchidectomy [267]. 3.5.4.2 Subfertility Subfertility is found in 36-39% of patients after torsion. Semen analysis may be normal in only 5-50% in longterm follow-up [257]. Early surgical intervention (mean torsion time less than thirteen hours) with detorsion was found to preserve fertility, but a prolonged torsion period (mean 70 hours) followed by orchiectomy jeopardised fertility [259]. Subfertility and infertility are consequences of direct injury to the testis after the torsion. This is caused by the cut-off of blood supply, but also by post-ischaemia-reperfusion injury that is caused after the detorsion when oxygen-derived free radicals are rapidly circulated within the testicular parenchyma [257]. 3.5.4.3 Androgen levels Even though the levels of FSH, luteinising hormone (LH) and testosterone are higher in patients after testicular torsion compared to normal controls, endocrine testicular function remains in the normal range after testicular torsion [260]. 3.5.4.4 Unanswered questions Although testicular torsion is a common problem, the mechanism of neonatal and prenatal torsion is still not exactly known, as well as whether fixation of the contralateral testicle in these cases is really necessary. The influence of an atrophied testicle on fertility is also unclear. Summary of evidence LE Diagnosis of testicular torsion is based on presentation and physical examination. Doppler US is an effective imaging tool to evaluate acute scrotum and comparable to scintigraphy and 2a dynamic contrast-enhanced subtraction MRI. Neonates with acute scrotum should be treated as surgical emergencies. 3

Recommendations Testicular torsion is a paediatric urological emergency and requires immediate treatment. In neonates with testicular torsion perform orchidopexy of the contralateral testicle. In prenatal torsion the timing of surgery is usually dictated by clinical findings. Base the clinical decision on physical examination. The use of Doppler ultrasound to evaluate acute scrotum is useful, but this should not delay the intervention. Manage torsion of the appendix testis conservatively. Perform surgical exploration in equivocal cases and in patients with persistent pain. Perform urgent surgical exploration in all cases of testicular torsion within 24 hours of symptom onset. In prenatal torsion the timing of surgery is usually dictated by clinical findings.

3.6

Strength rating Strong Weak Strong Strong Strong

Hypospadias

3.6.1 Epidemiology, aetiology and pathophysiology 3.6.1.1 Epidemiology The total prevalence of hypospadias in Europe is 18.6 new cases per 10,000 births (5.1-36.8) according to the recent EUROCAT registry-based study. This incidence was stable over the period of 2001 to 2010 [268, 269]. The mean worldwide prevalence of hypospadias according to an extended systematic literature review varies: Europe 19.9 (range: 1-464), North America 34.2 (6-129.8), South America 5.2 (2.8-110), Asia 0.6-69,

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Africa 5.9 (1.9-110), and Australia 17.1-34.8. There are conflicting data on the recent trends of prevalence – different trends in Europe and an increasing trend in the USA [270, 271]. 3.6.2 Risk factors Risk factors associated with hypospadias are likely to be genetic, placental and/or environmental [268, 269] (LE: 2b). Interactions between genetic and environmental factors may help explain non-replication in genetic studies of hypospadias. Single nucleotide polymorphisms seemed to influence hypospadias risk only in exposed cases [269, 272] (LE: 2b). • An additional family member with hypospadias is found in 7% of families, but this is more predominant in anterior and middle forms [272-275]. • Endocrine disorders can be detected in rare cases. • Babies with a low birth weight have a higher risk of hypospadias [272-275]. • Over the last 25 years, a significant increase in the incidence of hypospadias has been found. • Endocrines disruptors are one component of a multi-factorial model for hypospadias. • The use of oral contraceptives prior to pregnancy has not been associated with an increased risk of hypospadias in offspring, but their use after conception increased the risk of middle and posterior hypospadias [273-276] (LE: 2a). 3.6.3 Classification systems Hypospadias are usually classified based on the anatomical location of the proximally displaced urethral orifice: • distal-anterior hypospadias (located on the glans or distal shaft of the penis and the most common type of hypospadias); • intermediate-middle (penile); • proximal-posterior (penoscrotal, scrotal, perineal). The pathology may be different after skin release and should be reclassified accordingly. Anatomical location of the meatus may not always be enough to explain the severity and the complex nature of this pathology. Therefore, a simple classification related to severity of the problem, which considers penile length, glans size, shape, urethral plate quality and penile curvature is commonly used. In that classification there are two types: mild hypospadias (glanular or penile isolated hypospadias without associated chordee, micropenis or scrotal anomaly); severe hypospadias (penoscrotal, perineal hypospadias with associated chordee and scrotal anomalies). 3.6.4 Diagnostic evaluation Most hypospadias patients are easily diagnosed at birth (except for the megameatus intact prepuce variant which can only be seen after retraction of foreskin). Diagnosis includes a description of the local findings: • position, shape and width of the orifice; • presence of atretic urethra and division of corpus spongiosum; • appearance of the preputial hood and scrotum; • size of the penis; • curvature of the penis on erection. The diagnostic evaluation also includes an assessment of associated anomalies, which are: • cryptorchidism (in up to 10% of cases of hypospadias); • open processus vaginalis or inguinal hernia (in 9-15%). Severe hypospadias with unilaterally or bilaterally impalpable testis, or with ambiguous genitalia, requires a complete genetic and endocrine work-up immediately after birth to exclude DSD, especially congenital adrenal hyperplasia. Urine trickling and ballooning of the urethra requires exclusion of meatal stenosis. The relationship between the severity of the hypospadias and associated anomalies of the upper or lower urinary tract were not confirmed [277] (LE: 3). 3.6.5 Management 3.6.5.1 Indication for reconstruction and therapeutic objectives Differentiation between functionally necessary and aesthetically feasible operative procedures is important for therapeutic decision making. The indications for surgery are: • proximally located (ectopic) meatus causing ventrally deflected or spraying urinary stream; • meatal stenosis; • anterior curvature of the penis;

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• • • • •

cleft glans; rotated penis with abnormal cutaneous raphe; preputial hood; penoscrotal transposition; split scrotum.

Physical examination should check all anatomic components of the penis and evaluate the degree and nature of abnormality in each component. The examination should evaluate location of the meatus, the degree of proximal spongiosal hypoplasia, presence and degree of penile curvature, width and depth of the urethral plate, size of the glans, degree of ventral skin deficiency, availability of the foreskin and scrotal abnormalities like penoscrotal transposition and bifid scrotum. As all surgical procedures carry the risk of complications, thorough pre-operative counselling of the caregiver is crucial. To achieve an overall acceptable functional and cosmetic outcome, the penile curvature must be corrected and a neo-urethra of an adequate size with opening on the glans formed with proper skin coverage of the penile shaft [278] (LE: 4) (Figure 3). The use of magnifying spectacles and fine synthetic absorbable suture materials (6.0-7.0) are required. As in any penile surgery, exceptional prudence should be adopted with the use of cautery. Bipolar cautery is recommended. Knowledge of a variety of surgical reconstructive techniques, wound care and post-operative treatment are essential for a satisfactory outcome. 3.6.5.2 Pre-operative hormonal treatment There is a lack of high-quality evidence to support that pre-operative hormonal treatment with androgen stimulation improves surgical outcomes. Yet, this treatment in the form of systemic testosterone, topical testosterone, and derivatives like dihydrotestosterone (DHT) and hCG are commonly being used to increase glans size pre-operatively to allow better tubularisation of the urethral plate and decrease the incidence of glans dehiscence. This treatment is usually limited to patients with proximal hypospadias, a small appearing penis, reduced glans circumference or reduced urethral plate [276, 279, 280]. Studies have shown that it leads to significant enlargement of the glans and shaft of the penis (LE: 1b) [281, 282]. Moderate quality evidence from three randomised studies demonstrate significantly lower rates of urethracutaneous fistulae and re-operation rates in patients who received pre-operative hormonal treatment [283]. Pre-operative testosterone administration is most often well tolerated. Transient side effects on child´s behaviour, increased genital pigmentation, appearance of pubic hair, penile skin irritation and redness, increased erections and peri-operative bleeding have been reported, but no persistent side effects related to hormonal stimulation have been reported in the literature. There is also no evidence about possible effects on bone maturation [280, 283, 284]. There are concerns regarding the negative impacts of testosterone on wound-healing and increased bleeding during surgery. Cessation of therapy is recommended one or two months prior to surgery to avoid adverse effects during or after surgery [285]. 3.6.5.3 Age at surgery The age at surgery for primary hypospadias repair is usually 6-18 (24) months [278, 286, 287] (LE: 3). Age at surgery is not a risk factor for urethroplasty complication in pre-pubertal tubularised incised plate urethroplasty (TIP) repair [286] (LE: 2b). Complication rate after primary TIP repair was 2.5 times higher in adults than in the paediatric group according to a recent prospective controlled study [288] (LE: 2a). 3.6.5.4 Penile curvature If present, penile curvature is often released by degloving the penis (skin chordee) and by excision of the connective tissue of the genuine chordee on the ventral aspect of the penis in up to 70% [289]. The urethral plate has well vascularised connective tissue and does not cause curvature in most cases [290, 291]. The residual curvature is caused by corporeal disproportion and requires straightening of the penis, mostly using dorsal midline plication or orthoplasty (modification of the Nesbit plication with or without elevation of the neurovascular bundle). In more severe curvature (> 45°), which is often combined with a short urethral plate requiring transection, ventral penile lengthening is recommended to prevent shortening of the penis. This consists of a ventral transverse incision of the tunica albuginea extending from the 3 to 9 o´clock position patched with tunica vaginalis flap or graft, or in several short ventral corporotomies without grafting (LE: 2b) [292]. After the ventral lengthening, a shorter dorsal midline plication is usually added.

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According to a retrospective study, dorsal plication remained significantly associated with recurrent ventral curvature independently of the other factors. Ventral corporeal grafting for severe penile curvature gives good long-term results and safety profiles for erectile function [293] (LE: 2b). 3.6.5.5 Urethral reconstruction The mainstay of hypospadias repair is preservation of the well-vascularised urethral plate and its use for urethral reconstruction has become standard practice in hypospadias repair [291]. Mobilisation of the corpus spongiosum/urethral plate and the bulbar urethra decreases the need for urethral plate transection [292] (LE: 2b). If the urethral plate is wide, it can be tubularised following the Thiersch-Duplay technique. If the plate is too narrow to be simply tubularised, it is recommended relaxing the plate by a midline incision and its subsequent tubularisation according to the Snodgrass-Orkiszewski TIP technique. This technique has become the treatment of choice in distal- and mid-penile hypospadias [294-297]. If the incision of the plate is deep, it is recommended to cover the raw surface with inner preputial (or buccal) inlay graft in primary and secondary repairs [298]. This also enables extension of the incision beyond the end of the plate to prevent meatal stenosis [299, 300] (LE: 2a). For distal forms of hypospadias, a range of other techniques is available (e.g. Mathieu, urethral advancement) [301] (LE: 2b). The TIP technique has become an option for proximal hypospadias as well [294-297, 302]. However, urethral plate elevation and urethral mobilisation should not be combined with TIP repair because it results in focal devascularisation of the neo-urethra with symptomatic stricture development [303] (LE: 2b). The onlay technique using a preputial island flap is a standard repair, preferred in proximal hypospadias, if a plate is unhealthy or too narrow [289]. An onlay preputial graft is an option for single-stage repair [304] (LE: 2b). If the continuity of the urethral plate cannot be preserved, single or two-stage repairs are used. For the former, a modification of the tubularised flap (Duckett tube), such as a tube-onlay or an inlay-onlay flap, or onlay flap on albuginea are used to prevent urethral stricture [305-307] (LE: 3); alternatively the Koyanagi-Hayashi technique is used [308-311]. The two-stage procedure has become preferable over the past few years because of lower recurrence of ventral curvature and more favourable results with variable long-term complication rates [300, 305, 312-316]. 3.6.5.6 Re-do hypospadias repairs For re-do hypospadias repairs, no definitive guidelines can be given. All the above-mentioned procedures are used in different ways and are often modified according to the individual findings and needs of the patient.

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Figure 3: Algorithm for the management of hypospadias

Diagnosis at birth

Exclude DSD

Paediatric urologist

No reconstruction

Reconstruction required

Distal

Proximal

Chordee

Thiersch Duplay, TIP, Mathieu, MAGPI, advancement

No chordee

Urethral plate cut

Urethral plate preserved

Two-stage, tube-onlay Koyanagi repair

Onlay, TIP

DSD = disorders of sex development; TIP = tubularised incised plate urethroplasty; MAGPI = meatal advancement and glanuloplasty incorporated. 3.6.5.7 Penile reconstruction following formation of the neo-urethra Following formation of the neo-urethra, the procedure is completed by glansplasty and by reconstruction of the penile skin. If there is a shortage of skin covering, the preputial double-face technique or placement of the suture line into the scrotum according to Cecil-Michalowski is used. In countries where circumcision is not routinely performed, preputial reconstruction can be considered. Preputial reconstruction carries a risk of specific complications but does not seem to increase the risk of urethroplasty complications [317]. In TIP repair, the use of a preputial dartos flap reduces the fistula rate [294, 295] (LE: 2b). 3.6.5.8 Urine drainage and wound dressing Urine is drained transurethrally (e.g. dripping stent) or with a suprapubic tube. No drainage after distal hypospadias repair is another option [318, 319]. Circular dressing with slight compression, as well as prophylactic antibiotics during surgery, are established procedures [319] (LE: 4). Post-operative prophylaxis after hypospadias repair has limited benefit and it only reduces the risk of asymptomatic bacteriuria [320-322] (LE: 2b). There is no consensus on duration of stenting and dressing. 3.6.5.9 Outcome Some studies have tried to determine risk factors for complications after hypospadias repair. An analysis of prospectively collected data found glans size (width < 14 mm), proximal meatal location and re-operation as independent risk factors for urethral complication [319, 323]. Low surgeon volume independently increases the risk of fistula, stricture or diverticulum repair [319, 324] (LE: 3).

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A meta-analysis of complication rates of TIP repair found lower complication rates and incidence of re-operations in primary distal repairs (in 4.5%) than in primary proximal repairs (in 12.2%) and in secondary repair (in 23.3%) [294-297, 301, 319]. One should expect a predictable outcome with complication rates below 10% in distal hypospadias (fistula, meatal stenosis, dehiscence, recurrent ventral curvature, and haematoma) [324, 325]. A similar incidence of fistula (3.4-3.6%) can be expected after the Mathieu and TIP repairs of distal hypospadias [302, 326-328]. The complication rates of TIP and onlay repairs of primary severe hypospadias are similar, 24% and 27%, respectively. It is higher in free graft and in preputial island tube urethroplasty [289]. There is no strong evidence to suggest that the use of inlay grafts in TIP repair improves the outcome [329]. The complication rates of single-stage Koyanagi and Hayashi modification repairs go up 61%, according to a comparative study [308, 319]. Staged buccal mucosa graft requires a redo grafting in 13% of patients, after the second stage more than one third of patients have complications, mostly with some degree of graft fibrosis [327, 330]. A recent long-term study on two-stage flap repair showed a complication rate of 68% [319]; another study showed a re-operation rate of 28% [300, 319]. 3.6.6 Follow-up Long-term follow-up is necessary up to adolescence to detect urethral stricture, voiding dysfunctions and recurrent penile curvature, diverticula, glanular dehiscence [331]. Up to half of complications requiring re-operation present after the first year post-operatively [332] (LE: 2b). Obstructive flow curve is common after hypospadias repair and while most are not clinically significant, long-term follow-up is required [333-336] (LE: 2a). Urine flow is significantly lower in patients after hypospadias surgery, especially in those who had corrected chordee, but without significant association with lower urinary symptoms [337] (LE: 2a). Objective scoring systems have been developed in order to evaluate the results of hypospadias surgery (HOSE) [338] (LE: 2b) and cosmetic appearance (HOPE-Hypospadias Objective Penile Evaluation) [339] (LE: 2a). The Pediatric Penile Perception Score (PPPS) is a reliable instrument to assess penile self-perception in children after hypospadias repair and for appraisal of the surgical result by caregivers and uninvolved urologists [340] (LE: 2a). Cosmetic results were judged more optimistically by surgeons as compared to caregivers using validated tools [341]. Current scoring systems have deficiencies in terms of patient reported outcomes, the long term outcomes and sexual function [342]. Adolescents and adults, who have undergone hypospadias repair in childhood, have a slightly higher rate of dissatisfaction with penile size, especially proximal hypospadias patients, but their sexual behaviour is not different from that of control groups [343, 344] (LE: 2a-b). Another long-term follow-up of men born with hypospadias revealed, in a controlled study, that these patients are less satisfied with penile cosmetic outcome according to all parameters of the PPPS; there was a difference in penile length (9.7 vs. 11.6 cm) and more patients had lower maximum urinary flow. More prominent results were found in proximal hypospadias vs. controls [319, 345]. According to a systematic review of long-term patient satisfaction with cosmetic outcomes [346]: • patient perception of penile size does not differ greatly from the norm; • patients approaching puberty have a more negative perception and are more critical about the cosmetic outcomes of surgery; • patients report high levels of perception of deformity and social embarrassment. There is a wide range of parameters that are measured to assess outcome after hypospadias surgery in the literature. There is a need for age-specific core outcome set [347]. The majority of identified instruments focused on post-operative cosmetic satisfaction, with only one instrument considering urinary function, and no instruments evaluating sexual function and psychosocial sequelae [348]. 3.6.7

Summary of evidence and recommendations for the management of hypospadias

Summary of evidence The suggested age at surgery for primary hypospadias repair is 6 - 18 (24) months.

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The therapeutic objectives are to correct the penile curvature, to form a neo-urethra of an adequate size, to bring the new meatus to the tip of the glans, if possible, and to achieve an overall acceptable cosmetic appearance. Androgen stimulation therapy results in increased penile length and glans circumference. The complication rate is about 10% in distal and 25% in proximal hypospadias one-stage repairs. Higher and variable rates (between 28 and 68%) can occur in two-stage repairs. Sexual functions are usually well preserved but patients report high levels of perception of deformity and social embarrassment. Recommendations At birth, differentiate isolated hypospadias from disorders of sex development which are mostly associated with cryptorchidism or micropenis. Counsel caregivers on functional indications for surgery, aesthetically feasible operative procedures (psychological, cosmetic indications) and possible complications. In children diagnosed with proximal hypospadias and a small appearing penis, reduced glans circumference or reduced urethral plate, pre-operative hormonal androgen stimulation treatment is an option and the body of evidence to accentuate its harms and benefits is inadequate. For distal hypospadias, offer Duplay-Thiersch urethroplasty, original and modified tubularised incised plate urethroplasty; use the onlay urethroplasty or two-stage procedures in more severe hypospadias. A treatment algorithm is presented (Figure 3). Correct significant (> 30°) curvature of the penis. Ensure long-term follow-up to detect urethral stricture, voiding dysfunctions and recurrent penile curvature, ejaculation disorder, and to evaluate patient´s satisfaction. Use validated objective scoring systems to assist in evaluating the functional and cosmetic outcome.

3.7

4

1b 3 2b

Strength rating Strong Strong Weak

Weak

Strong Strong

Congenital penile curvature

3.7.1 Epidemiology, aetiology and pathophysiology Congenital penile curvature presents penile bending of a normally formed penis due to corporal disproportion. The incidence at birth is 0.6% and congenital penile curvature is caused by asymmetry of the cavernous bodies and an orthotopic meatus [349] because of developmental arrest during embryogenesis [350]. On the other hand, the incidence of clinically significant congenital penile curvature is much lower, because the extent of the curvature and its associated sexual dysfunction varies widely [351]. Most of the cases are ventral deviations (48%), followed by lateral (24%), dorsal (5%), and a combination of ventral and lateral (23%) [352]. Most ventral curvatures are associated with hypospadias due to chordee or ventral dysplasia of cavernous bodies [353]. Similarly, dorsal curvature is mostly associated with exstrophy/epispadias complex. Congenital penile curvature can decrease sexual quality of life in adults and successful repair can restore patients’ psychosocial and sexual wellbeing [354] Curvature > 30° is considered clinically significant; curvature > 60° may interfere with satisfactory sexual intercourse in adulthood (LE: 4). Minor penile curvature may be the result of ventral penile skin deficiency only and should be distinguished from corporal anomalies. For penile curvature associated with hypospadias or epispadias refer to the relevant chapters. 3.7.2 Diagnostic evaluation Penile curvature is frequently not documented until later in childhood since the penis only appears abnormal when erect. Patients are usually concerned with the aesthetic and/or functional aspects of their penis [355]. Besides exact history taking to exclude any possibility of acquired penile curvature (e.g. post-traumatic), a thorough clinical examination is mandatory. In addition, photo documentation of the erect penis clearly showing the curvature from different angles serves as a pre-requisite in pre-operative evaluation [356]. The exact degree of curvature is generally determined at the time of surgery using an artificial erection test. 3.7.3 Management The treatment is surgical, starting with an artificial erection to determine the degree of curvature and to check symmetry after the repair [357]. The ultimate goal of any surgical method used to correct the curvature is to achieve corpora of similar size. Various procedures are in use ranging from simple de-gloving and plication procedures, to corporal rotation, use of free dermal or tunica vaginalis grafts, to complete penile disassembly techniques [358, 359]. Reviews comparing the outcome of Nesbit/modified Nesbit procedures [360] to plication

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procedures [361] were able to demonstrate that while there is a decreased risk of complications and loss of sensation, it remains unclear whether plication techniques can lead to increased risk of recurrence [362, 363]. Altogether these methods include the risk of post-operative shortening of the penis with an average loss of 2.5 cm in stretched penile length depending on the pre-operative degree of curvature and the type of repair used [364-366]. Recently the non-corporotomy technique has been introduced with promising results enabling correction of any degree of ventral curvature with neither shortening of the penis nor the risk of post-operative erectile dysfunction [367]. 3.7.4

Summary of evidence and recommendations for the management of congenital penile curvature

Summary of evidence Isolated congenital penile curvature is relatively uncommon. Congenital penile curvature is often associated with hypospadias. Diagnosis is usually made late in childhood. The penis only appears abnormal when erect. Congenital penile curvature can cause aesthetic as well as functional sexual problems. Congenital penile curvature is treated with surgery. The goal of surgery is to achieve corpora of similar size. Recommendations Ensure that a thorough medical history is taken and a full clinical examination done to rule out associated anomalies in boys presenting with congenital curvature. Provide photo documentation of the erect penis from different angles as a prerequisite in the pre-operative evaluation. Perform surgery after weighing aesthetic as well as functional implications of the curvature. At the beginning as well as at the end of surgery, perform artificial erection tests.

3.8

LE 2a 2a 2a 1b 1b 1b 1b

LE 1a

Strength rating Strong

1b

Strong

2b

Weak

2a

Strong

Varicocele in children and adolescents

3.8.1 Epidemiology, aetiology and pathophysiology Varicocele is defined as an abnormal dilatation of testicular veins in the pampiniformis plexus caused by venous reflux. It is unusual in boys under ten years of age and becomes more frequent at the beginning of puberty. It is found in 14-20% of adolescents, with a similar incidence during adulthood. It appears mostly on the left side (78-93% of cases). Right-sided varicoceles are less common; they are usually noted only when bilateral varicoceles are present and seldom occur as an isolated finding [368-370]. Varicocele develops during accelerated body growth and increased blood flow to the testes, by a mechanism that is not clearly understood. Genetic factors may be present. An anatomic abnormality leading to impaired venous drainage is expressed by the considerable prevalence of the left side condition where the internal spermatic vein drains into the renal vein. Varicocele can induce apoptotic pathways because of heat stress, androgen deprivation and accumulation of toxic materials. Severe damage is found in 20% of adolescents affected, with abnormal findings in 46% of affected adolescents. Histological findings are similar in children or adolescents and in infertile men. In 70% of patients with grade II and III varicocele, left testicular volume loss was found. Several authors reported on reversal of testicular growth after varicocelectomy in adolescents [371, 372]. An average proportion of catch-up growth of 76.4% (range: 52.6-93.8%) has been found according to a meta-analysis [373] (LE: 2a). However, this may partly be attributable to testicular oedema associated with the division of lymphatic vessels [374] (LE: 2). In about 20% of adolescents with varicocele, fertility problems will arise [375]. The adverse influence of varicocele increases with time. Improvement in sperm parameters has been demonstrated after adolescent varicocelectomy [376-379] (LE: 1). 3.8.2 Classification systems Varicocele is classified into 3 grades [380]: • Grade I - Valsalva positive (palpable at Valsalva manoeuvre only); • Grade II - palpable (palpable without the Valsalva manoeuvre); • Grade III - visible (visible at distance).

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3.8.3 Diagnostic evaluation Varicocele is mostly asymptomatic, rarely causing pain. It may be noticed by the patient or caregivers, or discovered by the paediatrician at a routine visit. The diagnosis depends upon the clinical finding of a collection of dilated and tortuous veins in the upright posture; the veins are more pronounced when the patient performs the Valsalva manoeuvre. The size of both testicles should be evaluated during palpation to detect a smaller testis. Venous reflux into the plexus pampiniformis is diagnosed using Doppler US colour flow mapping in the supine and upright position [381]. Venous reflux detected on US only is classified as subclinical varicocele. To discriminate testicular hypoplasia, the testicular volume is measured by US examination or by orchidometer. In adolescents, a testis that is smaller by > 2 mL or 20% compared to the other testis is considered to be hypoplastic [382] (LE: 2). Extension of Wilms tumour into the renal vein and inferior vena cava can cause a secondary varicocele. A renal US should be routinely added in pre-pubertal boys and in isolated right varicocele (LE: 4). In order to assess testicular injury in adolescents with varicocele, supranormal FSH and LH responses to the luteinising hormone-releasing hormone (LHRH) stimulation test are considered reliable, because histopathological testicular changes have been found in these patients [378, 383]. 3.8.4 Management There is no evidence that treatment of varicocele at paediatric age will offer a better andrological outcome than an operation performed later. Beneficial effect of pubertal screening and treatment for varicocele regarding chance of paternity has been questioned according to a corresponding questionnaire in adult patients [384] (LE: 4). The recommended indication criteria for varicocelectomy in children and adolescents are [369]: • varicocele associated with a small testis; • additional testicular condition affecting fertility; • bilateral palpable varicocele; • pathological sperm quality (in older adolescents); • symptomatic varicocele [384]. Testicular (left + right) volume loss in comparison with normal testes is a promising indication criterion, once the normal values are available [385]. Repair of a large varicocele, causing physical or psychological discomfort, may also be considered. Other varicoceles should be followed-up until a reliable sperm analysis can be performed (LE: 4). Surgical intervention is based on ligation or occlusion of the internal spermatic veins. Ligation is performed at different levels: • inguinal (or subinguinal) microsurgical ligation; • suprainguinal ligation, using open or laparoscopic techniques [386-389]. The advantage of the former is the lower invasiveness of the procedure, while the advantage of the latter is a considerably lower number of veins to be ligated and safety of the incidental division of the internal spermatic at the suprainguinal level. For surgical ligation, some form of optical magnification (microscopic or laparoscopic) should be used because the internal spermatic artery is 0.5 mm in diameter at the level of the internal ring [386, 388]. The recurrence rate is usually < 10%. Lymphatic-sparing varicocelectomy is preferred to prevent hydrocele formation and testicular hypertrophy development and to achieve a better testicular function according to the LHRH stimulation test [374, 386, 387, 390] (LE: 2). The methods of choice are subinguinal or inguinal microsurgical (microscopic) repairs, or suprainguinal open or laparoscopic lymphatic-sparing repairs [386, 388, 391, 392]. Intrascrotal application of isosulphan blue was recommended to visualise the lymphatic vessels [393, 394]. In suprainguinal approach, an artery sparing varicocelectomy may not offer any advantage in regards to catch-up growth and is associated with a higher incidence of recurrent varicocele [395, 396]. Angiographic occlusion of the internal spermatic veins also meets the requirements of lymphatic sparing repair. It is based on retrograde or antegrade sclerotisation of the internal spermatic veins [397, 398]. However, although this method is less invasive and may not require general anaesthesia, it is associated with radiation burden, which is less controllable in the antegrade technique [369, 397, 398] (LE: 2). There is low to moderate level of evidence that radiological or surgical treatment of adolescent varicocele is associated with improved testicular size/growth and sperm concentration - based on current available RCTs. The ultimate effects on fertility and paternity rates are not known [399].

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Microsurgical varicocele repair in adolescents with varicocele significantly increases paternity rates and decreases time to conception post-operatively. Patients with varicocele who underwent microsurgical varicocele repair had increased sperm parameters and 3.63 times greater odds of paternity than controls who did not undergo varicocele surgery [400]. The Panel recently conducted a systematic review and meta-analysis regarding the treatment of varicocele in children and adolescents [401]. Of 1,550 articles identified, 98 articles including 16,130 patients were eligible for inclusion (12 RCTs, 47 NRSs and 39 case series). The key findings are summarised in the following paragraphs: The meta-analysis of the twelve RCTs revealed that varicocele treatment improved testicular volume (mean difference 1.52 ml, 95% CI 0.73-2.31) and increased total sperm concentration (mean difference 25.54, 95% CI 12.84-38.25) when compared with observation. Lymphatic sparing surgery significantly decreased hydrocele rates (p=0.02) and the OR was 0.08 (95% CI 0.01, 0.67). Due to the lack of RCTs, it was not possible to identify a surgical technique as being superior to the others. It remains unclear whether open surgery or laparoscopy is more successful for varicocele treatment (OR ranged from 0,13 to 2,84). The success rates of the treatment (disappearance of varicocele) were between 85.1% and 100% whereas the complication rates were between 0% and 29% in the included studies. The most common complication reported was hydrocele. Resolution of pain after treatment was more than 90% in the reported series. In conclusion, moderate evidence exists on the benefits of varicocele treatment in children and adolescents in terms of testicular volume and sperm concentration. Current evidence does not demonstrate superiority of any of the surgical/interventional techniques regarding treatment success. Lymphatic sparing surgery significantly decreases hydrocele formation. Long-term outcomes, including paternity and fertility, still remain unknown. 3.8.5

Summary of evidence and recommendations for the management of varicocele

Summary of evidence Varicocele becomes more frequent at the onset of puberty and is found in 14-20% of adolescents. Fertility problems are expected in up to 20% of adolescents with a varicocele. Pubertal patients with a left grade II and III varicocele have the left testis smaller in up to 70% of cases; in late adolescence the contralateral right testis also becomes smaller. After adolescent varicocelectomy, left testis catch-up growth and improvement in sperm parameters has been demonstrated. There is no evidence that treatment of varicocele at paediatric age will offer a better andrological outcome than an operation performed later. Division of testicular lymphatics leads to hydrocele in up to 40% and to testicular hypertrophy. Lymphatic sparing surgery significantly decrease hydrocele rates. Recommendations Examine varicocele in the standing position and classify into three grades. Use scrotal ultrasound to detect venous reflux without Valsalva manoeuvre in the supine and upright position and to discriminate testicular hypoplasia. In all pre-pubertal boys with a varicocele and in all isolated right varicoceles perform standard renal ultrasound to exclude a retroperitonal mass. Inform caregivers and patients and offer surgery for: • varicocele associated with a persistent small testis (size difference of > 2 mL or 20%); • varicocele associated with additional testicular condition affecting fertility (cryptorchidism, history of torsion, trauma); • varicocele associated with pathological sperm quality (in older adolescents); • symptomatic varicocele. Use some form of optical magnification (microscopic or laparoscopic magnification) for surgical ligation. Use lymphatic-sparing varicocelectomy to prevent hydrocele formation and testicular hypertrophy.

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LE 4

LE

1b 1a 1b 1b 1a

Strength rating Strong Strong Strong

2

Weak

2

Strong

1

Strong

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3.9

Urinary tract infections in children

3.9.1 Epidemiology, aetiology and pathophysiology Urinary tract infections (UTIs) represent the most common bacterial infections in children [402-404]. There are several classification systems used to define a UTI. In neonates, the symptoms differ in many aspects from those in infants and children. The prevalence is higher; there is a male predominance; infections caused by other organisms than Escherichia coli are more frequent; and there is a higher risk of urosepsis [405, 406]. In children presenting with urinary symptoms a pooled prevalence of UTI was 7.8% (CI: 6.6-8.9) [405]. The incidence varies depending on age and sex. One meta-analysis showed that in children presenting with fever in the first three months of life UTIs were present in 7.5% of girls, 2.4% (CI: 1.4-3.5) of circumcised boys, and 20.1% (CI: 16.8-23.4) of uncircumcised boys [405]. The incidence for boys is highest during the first 6 months of life (5.3%) and decreases with age to around 2% for the ages 0-6 years. In girls, UTIs are less common during the first 6 months of life (2%) and incidence increases with age to around 11% for the ages 0-6 years [407]. Associated risk factors for recurrent UTIs include bladder and bowel dysfunction (BBD), vesicoureteral reflux (VUR) and obesity [408-410]. In older children a delay in treatment is more often seen than in younger infants [411]. These risk factors in combination with delay in treatment have been associated with renal scarring [412]. Recurrent febrile UTIs, especially in combination with high-grade VUR, lead to renal scarring [413, 414]. Each new febrile UTI increases the risk of renal scarring with an incidence of renal scarring after the first UTI, of 2.8% (CI:1.2-5.8), 25.7% (CI:12.5-43.3) after the second infection and up to 28.6% (CI:8.4-58.1) after 3 or more febrile UTIs [414]. The leading causative organism for UTIs has been E. coli, but other bacteriae have been rising in prevalence. In a large European study E. Coli was found in less than 50% of urine cultures. Klebsiella pneumoniae, Enterobacter spp., Enterococcus spp., Pseudomonas spp., Proteus spp. and Candida spp. are more frequent in nosocomial infections than in community-acquired UTIs, even though, their prevalence has increased outside of the hospital setting [415]. Neonatal UTI is frequently complicated by bacteraemia. In a retrospective study, 12.4% of blood cultures from neonates admitted for UTI were positive for bacteraemia [416], however, it is less frequent in community-acquired than in nosocomial UTI [416, 417]. 3.9.2 Classification systems There are five widely used classification systems according to; site, severity, episode, symptoms and complicating factors. For acute treatment, site and severity are most important. 3.9.2.1 Classification according to site Lower urinary tract infection (cystitis) is an inflammatory condition of the urinary bladder mucosa with general signs and symptoms including infection, dysuria, frequency, urgency, malodorous urine, enuresis, haematuria, and suprapubic pain. Upper urinary tract infection (pyelonephritis) is a diffuse pyogenic infection of the renal pelvis and parenchyma. The onset of pyelonephritis is generally abrupt. Clinical signs and symptoms include fever (> 38°C), chills, costovertebral angle or flank pain, and tenderness. 3.9.2.2 Classification according to severity In a lower urinary tract infection, children may have only mild pyrexia; are able to take fluids and oral medication; are only slightly or not dehydrated; and have a good expected level of compliance. When a low level of compliance is expected, such children should be managed as those with severe UTI. In severe UTI, infection is related to the presence of fever of > 39°C, the feeling of being ill, persistent vomiting, and moderate or severe dehydration. Most severe UTIs are upper urinary tract infections. 3.9.2.3 Classification according to episode first/persistent/recurrent/breakthrough The first UTI may be a sign of anatomical anomalies. Anatomical evaluation is recommended (see below). Recurrent infection can be divided into unresolved and persistent infection. In unresolved infection, initial therapy is inadequate for elimination of bacterial growth in the urinary tract (inadequate therapy, inadequate antimicrobial urinary concentration [poor renal concentration/ gastrointestinal malabsorption], and infection involving multiple organisms with differing antimicrobial susceptibilities). Persistent infection is caused by re-emergence of bacteria from a site within the urinary tract coming from a nidus for persistent infection that cannot be eradicated (e.g. infected stones, non-functioning or poorly functioning kidneys/renal segments, ureteral stumps after nephrectomy, necrotic papillae, urachal cyst, urethral diverticulum, peri-urethral gland, vesicointestinal, rectourethral or vesicovaginal fistulas). The same pathogen is identified in recurrent infections, but episodes of sterile urine may occur during and shortly following antimicrobial treatment.

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A breakthough infection in patients under antibacterial prophylaxis is usually caused by resistent bacteria, parental non-compliance and/or severe urogenital anomalies [418, 419]. In re-infection, each episode can be caused by a variety of new infecting organisms, in contrast to bacterial persistence in which the same infecting organism is always isolated. However, the most common general pathogenic species is E. coli, which occurs in many different serotypes. Therefore, recurrent E. coli UTI does not equate to infection with the same organism. 3.9.2.4 Classification according to symptoms Children may have typical or atypical symptoms regarding a UTI. In neonates and infants the most commen symptoms are fever, vomiting, lethargy and/or irritability. Infants and children may have non-specific signs such as poor appetite, failure to thrive, lethargy, irritability, vomiting or diarrhoea. Toilet trained children may report cystitis symptoms along with fever/flank pain. Asymptomatic bacteriuria indicates attenuation of uropathogenic bacteria by the host, or colonisation of the bladder by non-virulent bacteria that are incapable of activating a symptomatic response (no leukocyturia, no symptoms). Asymptomatic UTI includes leukocyturia but no other symptoms. Symptomatic UTI, includes irritative voiding symptoms, suprapubic pain (cystitis), fever and malaise (pyelonephritis). Cystitis may represent early recognition of an infection destined to become pyelonephritis, or bacterial growth controlled by a balance of virulence and host response. 3.9.2.5 Classification according to complicating factors In uncomplicated UTI, infection occurs in a patient with a morphologically and functionally normal upper and lower urinary tract, normal renal function and competent immune system. This category includes mostly isolated or recurrent bacterial cystitis and is usually associated with a narrow spectrum of infecting pathogens that are easily eradicated by a short course of oral antimicrobial agents. Patients can be managed on an outpatient basis, with an emphasis on documenting resolution of bacteriuria, followed by elective evaluation for potential anatomical or functional abnormalities of the urinary tract [420]. A complicated UTI occurs in children with known mechanical or functional pathology of the urinary tract. Mechanical obstruction is commonly due to the presence of posterior urethral valves, strictures or stones, independent of their location. Functional obstruction often results from lower urinary tract dysfunction (LUTD) of either neurogenic or non-neurogenic origin and dilating VUR. Patients with complicated UTI require hospitalisation and parenteral antibiotics. Prompt anatomical evaluation of the urinary tract is critical to exclude the presence of significant abnormalities [421]. If mechanical or functional abnormalities are present, adequate drainage of the infected urinary tract is necessary. 3.9.3 Diagnostic evaluation 3.9.3.1 Medical history Medical history includes the question of a primary (first) or secondary (recurring) infection; possible malformations of the urinary tract (e.g. pre- or post-natal US screening); prior operation; family history; and, whether there is constipation or presence of lower urinary tract symptoms (LUTS). 3.9.3.2 Clinical signs and symptoms Neonates with severe UTI can present with non-specific symptoms (failure to thrive, jaundice, hyperexcitability) and without fever. In neonates it is important to rule out a co-existing meningitis [422]. Urinary tract infection is the cause of fever in 4.1-7.5% of children who present to a paediatric clinic [423, 424]. Septic shock is unusual, even with very high fever. Signs of a UTI may be vague and unspecific in small children, but later on, when they are more than two years old, frequent voiding, dysuria and suprapubic, abdominal or lumbar pain can be detected. 3.9.3.3 Physical examination Physical examination includes a general examination of the throat, lymph nodes, abdomen (constipation, palpable and painful kidney, or palpable bladder), flank, the back (stigmata of spina bifida or sacral agenesis), genitalia (phimosis, labial adhesion, vulvitis, epididymo-orchitis), measurement of body weight and temperature. 3.9.3.4 Urine sampling, analysis and culture Urine sampling has to be performed before any antimicrobial agent is administered. The technique for obtaining urine for urinalysis as well as culture affects the rate of contamination, which influences interpretation of the results. Especially in early infancy, it can be challenging and depends on the mode of urine sampling [425].

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3.9.3.4.1 Urine sampling Urine must be collected under defined conditions and investigated as soon as possible to confirm or exclude UTI, especially in children with fever. In neonates, infants and non-toilet-trained children, there are four main methods with varying contamination rates and invasiveness to obtain urine: (1) Plastic bag attached to the cleaned genitalia: Although this technique is most often used in daily practice, contamination rates are high with around 50-60% [426]. It is helpful when the culture results are negative. Also, if the dipstick is negative for both leukocyte esterase and nitrite, or microscopic analysis is negative for both pyuria and bacteriuria, UTI can be excluded without the need for confirmatory culture [427]. (2) Clean-catch urine (CCU) collection: The infant is placed in the lap of a caregiver or member of the nursing staff, who holds a sterile foil bowl underneath the infant’s genitalia. The infant is offered oral fluids and urine collection is awaited [428]. Suprapubic tapping alternated with paravertebral lumbar massage can stimulate sponateous voiding [426, 429]. There seems to be a good correlation between the results of urine culture obtained by this method and suprapubic aspiration (SPA), with a false-positive rate of 5% and false-negative rate of 12% [428, 430]; however, the contamination rate is higher for CCU with up to 26% compared to catheterisation 10% and SPA 1% [426, 431]. In one prospective cohort study in infanty below the age of 6 months, the success rate was 49% and the contamination rate 16% with some differences in the culture results between those obtained by CCU and those by more inavsive methods [432]. (3) Transurethral bladder catheterisation: is the fastest and safest method to obtain a reliable urine sample for microscopic and bacteriological evaluation to rule out or to document a UTI in non-toilet trained infants and children. (4) Suprapubic bladder aspiration: This is the most invasive but also the most sensitive method to obtain an uncontaminated urine sample in this age group [433, 434]. For suprapubic puncture ultrasound imaging should be performed to asses bladder filling. A two-step procedure where the CCU is screened and a catheter or SPA confirmation of the positive screens is used can lead to a reduction in invasive procedures [426, 431]. In older, toilet-trained children who can void on command, after carefully retracting the foreskin and cleaning the glans penis in boys and spreading the labia and cleaning the peri-urethral area in girls, the use of clean catch, especially midstream urine, could be an acceptable technique for obtaining urine. After cleaning the urethral meatus and perineum with gauze and liquid soap twice, the risk of contamination was reduced from 23.9% (41/171) to 7.8% (14/171) in a randomised trial [435]. 3.9.3.4.2 Urinalysis There are three methods that are commonly used for urinalysis: (1) Dipsticks: These are appealing because they provide rapid results, do not require microscopy, and are ready to use. Leukocyte esterase (as a surrogate marker for pyuria) and nitrite (which is converted from dietary nitrates by most Gram-negative enteric bacteria in the urine) are the most frequent markers, and are usually combined in a dipstick test. The conversion of dietary nitrates to nitrites by bacteria takes approximately four hours in the bladder [430, 436]. Using only nitrate sticks to screen febrile children < 2 years of age has a too low sensitivity and relevant UTIs can be missed. However, the specificity is high for children at any age [437, 438]. In febrile infants < 90 days old urine dipstick tests using CCU samples can be used for screening for a UTI when nitrites and leukocyte esterase combined are used with a sensitivity of 86% and a specificity of 80% [439]. (2) Microscopy: This is the standard method of assessing pyuria after centrifugation of the urine with a threshold of five white blood cells (WBCs) per high-power field (25 WBC/μL) [440]. In uncentrifuged urine, > 10 WBC/μL has been demonstrated to be sensitive for UTI [441] and this could perform well in clinical situations [442]. However, this is rarely done in an outpatient setting. No significant differences was found between dipsticks and microscopy testing for UTI [438]. A meta-analysis showed, that only microscopy with Gram staining has a higer sensitivity compared to dipsticks [443]. (3) Flow imaging analysis technology: This is being used increasingly to classify particles in uncentrifuged urine specimens [444]. The numbers of WBCs, squamous epithelial cells and red cells correlate well with those found by manual methods [430]. Flow cytometry-based bacterial and leukocyte count analysis when using a cut-off value of 250 bacteria/uL in the presence of leukocyturia has a sensitivity of 0.97 and specificity of 0.91 for diagnosing UTI [445].

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3.9.3.4.3 Urine culture After negative results for dipstick, microscopic or automated urinalysis, urine culture is generally not necessary, especially if there is an alternative source of fever. If the dipstick result is positive, confirmation by urine culture is strongly recommended. It is unclear what represents a significant UTI. In patients with a severe UTI, ≥ 105 cfu/mL can be expected. However, the count can vary and be related to the method of specimen collection, diuresis, and time and temperature of storage until cultivation occurs [406]. Clean-catch urine, midstream and catheterisation urine cultures can be considered positive as 103 - 104 cfu/mL in a monoculture, and any counts obtained after SPA should be considered as significant. Mixed cultures are indicative of contamination. In febrile children < 4 months of age a cut-off value of 103 cfu/mL can be used when clinical and laboratory findings match and a correct sampling method has been used [446]. A negative culture with the presence of pyuria may be due to incomplete antibiotic treatment, urolithiasis, or foreign bodies in the urinary tract, and infections caused by Mycobacterium tuberculosis or Chlamydia trachomatis. A flowchart was developed as guidance during the basic diagnostic evaluation and subsequent management of febrile children with clinical symptoms of UTI, Figure 4. Figure 4: D  iagnostic evaluation and subsequent management of a febrile child with clinical symptoms of UTI Febrile child with clinical symptoms

Physical examinaon

Blood sample (Blood cell count + CRP +/- Procalcitonin

Proper urine sampling & Urinalysis (Dipsck +/- Microscopy +/- Flow-imaging analysis)

Nitrate -ve and leukocyte -ve / Microscopy -ve / Flow imaging -ve

Nitrate +ve and/or leukocyte +ve / Microscopy +ve / Flow imaging +ve

Exclude other causes

Urine culture

Start AB treatment following anbacterial stewardship

Figure 5

CRP = C-reactive protein; AB = antibiotic. 3.9.3.5 Imaging 3.9.3.5.1 Ultrasound Renal and bladder US within 24 hours is advised in infants with febrile UTI to exclude obstruction of the upper and lower urinary tract. Abnormal results are found in 15% of cases, and 1-2% have abnormalities that require prompt action (e.g., additional evaluation, referral or surgery) [427]. When a renal US is performed in all children presenting with a UTI, 7% will have an abnormal US warranting further investigations [447]. The sensitivity to detect high-grade VUR with US was found to be 0.59 (CI: 0.45-0.72) with a specificity of 0.79 (CI: 0.65-0.87) [448]. Renal ultrasound should be performed before and after voiding. Post-void residual (PVR) urine should be measured in toilet-trained children to exclude voiding abnormalities as a cause of UTI. Elevated PVR urine volume predicts recurrence of UTIs in toilet-trained children [449]. When peri-renal or psoas abcesses or renal masses are seen on US, it is important to consider xanthogranulomatous pyelonephritis, and subsequent CT imaging is proposed [450].

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3.9.3.5.2 Radionuclide scanning/MRI Changes in dimercaptosuccinic acid (DMSA) clearance during acute UTI indicate pyelonephritis or parenchymal damage, correlated with the presence of dilating reflux and the risk of further pyelonephritis episodes, breakthrough infections [451] and future renal scarring. In the acute phase of a febrile UTI (up to four to six weeks), DMSA-scan can demonstrate pyelonephritis by perfusion defects. Renal scars can be detected after three to six months [452]. Diffusion-weighted MRI has shown to accurately diagnose acute pyelonephritis and reveal late renal scars and could be an alternative to DMSA; therefore, avoiding radion burden [453]. The average effective radiation dose of a single DMSA scan was 2.84 (1-12) mSv in one study [454]. These findings are different in neonates. After the first symptomatic, community-acquired UTI, the majority of renal units with VUR grade III or higher had normal early DMSA scanning [455]. The sensitivity of the DMSA scan to detect VUR is 0.75 (CI:0.67-0.81) with a specificity of 0.48 (CI: 0.38-0.57), and a negative DMSA scan resulting in a very low probability of high-grade VUR [456]. 3.9.3.5.3 Voiding cystourethrography/urosonography The optimum method to exclude or confirm VUR is VCUG. The timing of VCUG does not influence the presence or severity of VUR [457]. Performance of early VCUG in patients with proven sterile urine does not cause any significant morbidity [458]. Using harmonic voiding urosonography may be an alternative to the standard VCUG avoiding radiation [459]. Visulatisation of the urethra may be difficult with this technique. It is important to diagnose high-grade VUR after the first UTI since this is an important risk for renal scarring. On the other hand, physicians want to avoid unnecessary VCUG investigations at the same time, given its invasive character and radiation burden [447, 460]. Various studies have investigated the risk factors for high-grade VUR and a top down approach is feasible. The most important risk factors for high-grade VUR and subsequent renal scarring are: abnormal renal US, high fever UTI and non-E. Coli infections. Different top down strategies with selective VCUG investigations have been proposed [461-465]. Based on these studies we recommend the following updated diagnostic strategy (see Figure 5). Figure 5: Diagnosis strategy for first febrile UTI First febrile UTI

Renal and bladder ultrasound

Normal findings

E. Coli infecon

Children >12 months

Imaging aer recurrent febrile UTI

Non-E. Coli infecon

Infants

Exclusion of VUR (by imaging)

Abnormal findings (e.g. dilataon of upper tract/abscess formaon/obstrucng stone)

Complicated UTI close monitoring + i.v. anbiocs

Good clinical response

Crical clinical status/ no response

Further evaluaon of upper tract

Urinary diversion (nephrostomy/ JJ/catheter)

Toilet trained children Exclude BBD

UTI = urinary tract infection; VUR = vesicoureteral reflux; i.v. = intravenous.

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3.9.4 Management 3.9.4.1 Administration route of antibacterial therapy The choice between oral and parenteral therapy should be based on patient age; clinical suspicion of urosepsis; illness severity; refusal of fluids, food and/or oral medication; vomiting; diarrhoea; non-compliance; and complicated pyelonephritis (e.g. urinary obstruction). As a result of the increased incidence of urosepsis and severe pyelonephritis in newborns and infants aged less than two months, parenteral antibiotic therapy is recommended. Electrolyte disorders with life-threatening hyponatraemia and hyperkalaemia based on pseudohypoaldosteronism can occur in these cases [466, 467]. The choice of agent is also based on local antimicrobial sensitivity patterns, and should later be adjusted according to sensitivity-testing of the isolated uropathogen [430]. Not all available antibiotics are approved by national health authorities, especially in infancy. When recent urinary cultures are available use these sensitivity patterns in the choice for treatment. In children who require intravenuous treatment tobramycin or gentamicin is recommended if there is normal kidney function. When abnormal kidney function is suspected, ceftriaxon or cefotaxime are alternative treatment options. In children who can receive oral treatment without any known resistant urinary cultures, cefixime or amoxicillin-clavulanate are the empirical treatment options [468]. Some studies have demonstrated that once daily parenteral administration of gentamicin or ceftriaxone in a day treatment centre is safe, effective and cost-effective in children with UTI [469-471]. Delaying treatment in children with a febrile UTI for more than 48-72 hours increases the risk of renal scars [412, 472]. 3.9.4.2 Duration of therapy Prompt adequate treatment of UTI can prevent the spread of infection and renal scarring. In newborns and young infants with a febrile UTI, up to 20% may have a positive blood culture [416, 421]. Children with bacteremia did not show significant clinical differences with non-bacteremic infants, but did receive longer parental treatment [473]. In late infancy, there are no differences between strategies regarding the incidence of parenchymal scars, as diagnosed with DMSA scan [474]. Outcomes of short courses (one to three days) are inferior to seven to fourteen-day courses [430]. However, a simple cystitis can be treated with 3-5 days of antibiotics [468]. No significant difference in recurrent UTIs and rehospitalisation was found between seven day parental treatment and longer regimens for bacteremic UTI in younger infants [475]. In young infants a short course of parental treatment with early conversion to oral antibiotics may be considered. The use of exclusively oral therapy with a third-generation cephalosporin (e.g. cefixime or ceftibuten) has been demonstrated to be equivalent to the usual two to four days intravenous therapy followed by oral treatment [476-479]. Similar data have been shown for amoxicillin-clavulanate [480]. If ambulatory therapy is chosen, adequate surveillance, medical supervision and, if necessary, adjustment of therapy must be guaranteed. In the initial phase of therapy, a close ambulant contact to the family is advised [481]. In complicated UTI, uropathogens other than E. coli, such as Proteus mirabilis, Klebsiella spp., Pseudomonas aeruginosa, enterococci and staphylococci are more often the causative pathogens [421]. A temporary urinary diversion (transurethral catheter, suprapubic cystostomy, percutaneous nephrostomy or ureteral stenting) might be required in case of failure of conservative treatment in obstructive uropathy. Children with acute focal bacterial nephritis often present without pyyuria and significant bacteriuria. For the majority of children, the pathogenesis is related to ascending infection due to pre-existing uropathy, especially VUR or urinary obstruction. Initial management consists of broad-spectrum antibiotics with good tissue penetration. A treatment regimen of a total of 3 weeks with initial intravenous and subsequently oral therapy tailored to the pathogen identified in culture is recommended [482]. 3.9.4.3 Antimicrobial agents There is a great difference in the prevalence of antibiotic resistance of uropathogenic E. coli in different countries, with increased high resistance patterns in countries outside of the Organisation for Economic Co-operation and Development (OECD) [483]. There are upcoming reports of UTIs caused by extended spectrum ß-lactamase-producing enterobacteriaceae (ESBL) in children, with pooled numbers of UTI caused by ESBL producing bacteria of around 14% [484]. Within OECD countries the prevalence of resistance was 53% for ampicillin, 24% for trimethoprim, 8% for co-amoxiclav, 2% for ciproxin and 1% for nitrofurantoin [483]. Several risk factors and determinants for UTIs caused by ESBL and non-E. Coli bacteriae have been identified: history of infection, recent hospitalisation, short-term exposure to antiobiotics, and prophylaxis [483, 485, 486]. Overall, oral nitrofurantoin seems to be a good empirical choice in the treatment of cystitis [487]. The choice of antibiotics should be guided by good antibiotic stewardship. It is important to be aware of the local resistance patterns. These are variable between countries and moreover between hospitals. Local antibiotic protocols and web-based recommendations can guide the choice for type of antibiotic therapy. The individual patient’s previous urine cultures should also be taken into account in this decision. The daily dosage of antibiotics is depended on the age, weight of the child as well as on renal and liver function.

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3.9.4.4 Preventative measures Recurrent UTIs are problematic because the symptoms are bothersome to children and recurrent febrile UTIs will also result in renal scarring [414]. Therefore, it is important to prevent the incidence of recurrent UTIs. 3.9.4.4.1 Chemoprophylaxis Chemoprophylaxis is commonly used to prevent UTIs in children. However, with the increasing bacterial resistance numbers, it should be carefully considered which patients should receive antibacterial prophylaxis. The evidence for the use of antibacterial prophylaxis has been conflicting. Its use causes a reduction of the number of recurrent symptomatic UTIs, but long-term use of antibacterial prophylaxis has also been associated with increased microbial resistance [418, 488]. Its use did not reduce newly acquired renal damage in children with first or second UTI [488]. However, when used in patients with anatomic abnormalities of the urinary system a reduction in UTIs and subsequent renal scarring was shown [418, 488]. In children with BBD and VUR, a benefit was seen in the reduction of recurrent UTI with the use of antomicrobial prophylaxis [489, 490] (see also Chapter 3.14 on VUR). For the specific group of patients with incomplete bladder emptying with properly performed clean intermittent catheterisation but still suffering from recurrent UTIs the intravesical application of gentamycin has proven to be effective [491]. Table 1:

Drugs for antibacterial prophylaxis*

Substance Trimethoprim** Trimethoprim Sulfamethoxazole Sulfamethoxazole Nitrofurantoin** Cefaclor Cefixim

Prophylactic dosage (mg/kg bw/d) 1 1-2 10-15 1-2 1-2 10 2

Limitations in neonates and infants Not recommended under six weeks of age Not recommended under two months of age Until three months of age Not recommended under two months of age No age limitations Preterms and newborns

* Reproduced with permission from the International Consultation on Urological Diseases (ICUD), International Consultation on Urogenital Infections, 2009. Copyright© by the European Association of Urology [492]. ** S  ubstances of first choice are nitrofurantoin and trimethoprim. In exceptional cases, oral cephalosporin can be used. 3.9.4.4.2 Dietary supplements Cranberry, mostly as juice, has been shown to prevent UTIs in healthy children, while in children with urogenital abnormalities, cranberries appear to be just as effective as antibiotic prophylaxis [493]. The results for probiotics are somewhat more conflicting, with one systematic review not ruling out any effect [298] and a RCT showing promising results in children with normal urogenital anatomy [494]. A meta-analysis could not demonstrate a beneficial effect, only as an adjuvant to antibiotic prophylaxis [495]. Other supplements of interest were Vitamin A, which showed promising results in preventing renal scarring in children with acute pyelonephritis [496, 497]. The use of Vitamin E could possibly improve the symptoms of UTI [498]. More studies into these supplements are warranted. 3.9.4.4.3 Preputium A risk reduction of recurrent UTI regarding the preputium has been shown in two studies. When a physiologic phimosis is present in boys with a UTI the use of steroid cream significantly reduced recurrent UTIs [499]. In boys with recurrent UTIs and hydronephrosis present, 10 boys would need to be circumcised to prevent one UTI [34]. 3.9.4.4.4 Bladder and bowel dysfunction Bladder and bowel dysfunction is a risk factor for which each child with UTI should be screened upon presentation [409]. Normalisation of micturition disorders or bladder overactivity is important to lower the rate of UTI recurrence. If there are signs of BBD at infection-free intervals, further diagnosis and effective treatment are strongly recommended [490]. Treatment of constipation leads to a decrease in UTI recurrence and a multidisciplinary approach is recommended [409, 489, 490]. Therefore, exclusion of BBD is strongly recommended in any toilet-trained child with febrile and/or recurrent UTI, and it should be treated (For treatment see chapter for LUTS).

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3.9.4.5 Monitoring of UTI With successful treatment, urine usually becomes sterile after 24 hours, and leukocyturia normally disappears within three to four days. Normalisation of body temperature can be expected within 24-48 hours after the start of therapy in 90% of cases. In patients with prolonged fever and failing recovery, treatment-resistant uropathogens or the presence of congenital uropathy or acute urinary obstruction should be considered. Repeated US examination is recommended in these cases. Procalcitonin (among other laboratory inflammatory parameters such as C-reactive protein and leukocyte count) can be used as reliable serum marker for early prediction of renal parenchymal inflammation [500]. A cut-off value of serum procalcitonin of 1.0 ng/mL has been shown to be predictive of acute pyelonephritis in young children [501]. In patients with febrile UTI, serum electrolytes and blood cell counts should be followed up. 3.9.5

Summary of evidence and recommendations for the management of UTI in children

Summary of evidence Urinary tract infection represents the most common bacterial infection in children less than 2 years of age. The incidence varies depending on age and sex. Classifications are made according to the site, episode, severity, symptoms and complicating factors. For acute treatment, site and severity are most important. The number of colony forming units in the urine culture can vary, however, any colony count of one specimen indicates a high suspicion for UTI. Due to increasing resistance numbers good antibiotic stewardship should guide the choice of antibiotics, taking into account local resistance patterns, old urine cultures (when available) and clinical parameters. Preventive measures against recurrent UTIs include: chemoprophylaxis (oral and intravesical), cranberries, probiotics and Vitamin A and E. Urinalysis by dipstick yields rapid results, but it should be used with caution. Microscopic investigation is the standard method of assessing pyuria after centrifugation. During acute UTI both DMSA and diffusion-weighted MRI can confirm pyelonephritis or parenchymal damage. Recommendations Take a medical history, assess clinical signs and symptoms and perform a physical examination to diagnose children suspected of having a urinary tract infection (UTI). Exclude bladder- and bowel dysfunction in any toilet-trained child with febrile and/or recurrent UTI. Clean catch urine can be used for screening for UTI. Bladder catheterisation and suprapubic bladder aspiration to collect urine can be used for urine cultures. Do not use plastic bags for urine sampling in non-toilet-trained children since it has a high risk of false-positive results. Midstream urine is an acceptable technique for toilet-trained children. The choice between oral and parenteral therapy should be based on patient age; clinical suspicion of urosepsis; illness severity; refusal of fluids, food and/or oral medication; vomiting; diarrhoea; non-compliance; complicated pyelonephritis. Treat febrile UTIs with four to seven day courses of oral or parenteral therapy. Treat complicated febrile UTI with broad-spectrum antibiotics. Offer long-term antibacterial prophylaxis in case of high susceptibility to UTI and risk of acquired renal damage and lower urinary tract symptoms. In selected cases consider dietery supplements as an alternative or add-on preventive measure. In infants with febrile UTI use renal and bladder ultrasound to exclude obstruction of the upper and lower urinary tract within 24 hours. In infants, exclude vesicoureteral reflux after first epidose of febrile UTI with a non-E. Coli infection. In children more than one year of age with an E. Coli infection, exclude VUR after the second febrile UTI.

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3.10

Day-time lower urinary tract conditions

3.10.1 Terminology, classification, epidemiology and pathophysiology Urinary incontinence in children may be caused by congenital anatomical or neurologic abnormalities such as ectopic ureter, bladder exstrophy or myelomeningocele (MMC). In many children, however, there is no such obvious cause for the incontinence, and they are referred as having functional bladder problems. The most recent International Children’s Continence Society (ICCS) document suggests using the term day-time lower urinary tract (LUT) conditions to group together all functional bladder problems in children. Normal storage and emptying of the bladder at a socially accepted place and time is mostly achieved by age three to four. Children with LUT conditions would present with failure to achieve continence (being still wet after the age of four), urgency, weak stream, hesitancy, frequency and accompanied UTIs. Isolated nighttime wetting without any day-time symptoms is known as ‘enuresis’ and considered as a different entity (see chapter 3.11) [502]. As different studies have used varying definitions and criteria, it is difficult to give reliable percentages regarding the incidence of this problem. Reported prevalence ranges widely from 1% to 20% [503-511]. Due to increasing awareness and better access to specialised health care, the prevalence seems to be increasing [512, 513]. Lower urinary tract conditions in children may be due to disturbances of the filling phase, the voiding phase or a combination of both in varying severity. Mainly the conditions are divided into either overactive bladder (OAB) or dysfunctional voiding. They can, of course, coincide and one may even be causative of the other. Dysfunctional bowel emptying may also be part of the clinical problems and BBD is the term used to cover concomitant bladder and bowel disturbances. Lower urinary tract conditions are considered to be the result of incomplete or delayed maturation of the bladder sphincter complex. The pons is considered to be responsible for detrusor sphincter co-ordination while the cortical area is responsible for inhibition of the micturition reflex and voluntary initiation of micturition. Therefore overactivity would be the result of delayed maturation of cortical control, while dysfunctional voiding would be the result of non-maturation of the co-ordination. Detrusor overactivity should not be considered as a sole bladder based problem but more a symptom of a centrally located dysfunction affecting bladder, bowel and even mood and behaviour [514]. A link between LUT and behavioural disorders such as ADHD (attention deficit/ hyperactivity disorder) has also been shown [515-517]. 3.10.1.1 Filling-phase (storage) dysfunctions In filling-phase dysfunctions, the detrusor can be overactive, as in OAB, or underactive, as in underactive bladder (UAB). Overactivity of the bladder is the most common problem, seen mostly around five to seven years of age. This may lead to disturbances characterised by urgency, frequency and at times urgency incontinence. Some children habitually postpone micturition leading to voiding postponement. Therefore, holding manoeuvres such as leg crossing and squatting can often be seen in this group. Recurrent UTIs are common and high-pressure state of the bladder can be a cause of VUR. Constipation can be an additional aetiological factor, which needs to be assessed. In children with an underactive detrusor, voiding occurs with reduced or minimal detrusor contractions with post-void residuals. Urinary tract infections, straining to void, constipation and incontinence is common. Incontinence often occurs when the bladder is over-distended in the form of overflow incontinence. 3.10.1.2 Voiding-phase (emptying) dysfunctions In voiding-phase (emptying), incomplete relaxation or tightening of the sphincteric mechanism and pelvic floor muscles results in staccato voiding pattern (continuous urine flow with periodic reductions in flow rate precipitated by bursts of pelvic floor activity) or an interrupted voiding pattern (unsustained detrusor contractions resulting in infrequent and incomplete voiding, with micturition in fractions). The general term for this condition is dysfunctional voiding and is associated with elevated bladder pressures and PVRs. Symptoms will vary depending on the severity of inco-ordination between bladder and the sphincter. Staccato voiding is in less severe forms and interrupted voiding and straining is in more severe forms. The co-existence of constipation and LUTD and recurrent UTI is well described [518]. There is no evidence to conclude if bladder problems or bowel problems are the leading cause. The prevalence of constipation in older children varies from 5 to 27%. Approximately 90% of them being functional constipation without an organic cause In children with functinal constipation the prevelance of bladder symptoms have been shown to be as high as 64% [519, 520].

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In incomplete emptying, high voiding pressures generated by bladder working against a functional obstruction caused by non-relaxing sphincter may induce not only UTIs but also VUR. It is been shown that LUTD is more significant for the occurrence of UTI than VUR itself [521]. In the majority of children with dysfunctional voiding the recurrent infections disappear following successful treatment, which confirms the hypothesis that dysfunctional voiding is the main factor responsible for the infections. Spontaneous resolution of VUR may also be seen after successful treatment of dysfunctional voiding. 3.10.2 Diagnostic evaluation The evaluation of LUT conditions includes medical and voiding history (bladder diaries and structured questionnaires), a physical examination, a urinalysis, and uroflowmetry with PVR. The upper urinary tract (UUT) needs to be evaluated in children with recurrent infections and dysfunctional voiding. Uroflowmetry can be combined with pelvic floor electromyography to demonstrate overactivity of the pelvic floor muscles during voiding. Urodynamic studies are usually reserved for patients with therapy resistant dysfunctional voiding and those not responding to treatment who are being considered for invasive treatment [517, 522-525]. In addition to a comprehensive medical history a detailed voiding diary provides documentation of voiding and defecation habits, frequency of micturition, voided volumes, night-time urine output, number and timing of incontinence episodes, and fluid intake. A voiding diary should at least be done for two days, although longer observation periods are preferred. A voiding diary provides information about storage function and incontinence frequency, while a pad test can help to quantify the urine loss. In the paediatric age group, where the history is taken from both the caregivers and child together, a structured approach is recommended using a questionnaire. Many signs and symptoms related to voiding and wetting will be unknown to the caregivers and should be specifically requested, using the questionnaire as a checklist. Some symptom scorings have been developed and validated [526, 527]. Although the reliability of questionnaires are limited they are practical in a clinical setting to check the presence of symptoms and have also been shown to be reliable to monitor the response to treatment. History taking should also include assessment of bowel function. For evaluation of bowel function in children, the Bristol Stool Scale is an easy-to-use tool [528, 529]. Urinalysis and urinary culture are essential to evaluate for UTI. Since transient voiding symptoms are common in the presence of UTI, exclusion of UTI is essential before further management of symptoms. During clinical examination, genital inspection and observation of the lumbosacral spine and the lower extremities are necessary to exclude obvious uropathy and neuropathy. Uroflowmetry with PVR evaluates the emptying ability, while an UUT US screens for (secondary) anatomical changes. A flow rate which reaches its maximum quickly and levels off (‘tower shape’) may be indicative of over-active bladder whereas interrupted or staccato voiding patterns may be seen in dysfunctional voiding. Plateau uroflowmetry patterns are usually seen in anatomic obstruction of flow. A single uroflowmetry test may not always be representative of the clinical situation and multiple uroflowmetry tests, which all give a similar result, are more reliable. Uroflowmetry examination should be done when there is desire to empty the bladder and the voided volume should at least be 50% of the age-expected capacity [(age in years) + 1] x 30 mL for the children. While testing the child in a clinical environment, the impact of stress and mood changes on bladder function should also be taken into account [530, 531]. In the case of treatment failure re-evaluation is warranted and (video)-urodynamic (VUD) studies and neurological evaluation may be considered. Sometimes, there are minor, underlying, urological or neurological problems, which can only be suspected using VUD. In these cases, structured psychological interviews to assess social stress should be added [532] (LE: 1b). Video-urodynamics may also be used as initial investigational tool in patients with suspicion of reflux. In this case reflux may be observed along with bladder dynamics. In the case of anatomical problems, such as posterior urethral valve (PUV) problems, syringocoeles, congenital obstructive posterior urethral membrane (COPUM) or Moormann’s ring, it may be necessary to perform cystoscopy with treatment. If neuropathic disease is suspected, MRI of the lumbosacral spine and medulla can help to exclude tethered cord, lipoma or other rare conditions. 3.10.3 Management The treatment of LUTD involves a multimodal approach, involving strategies such as behavioural modification, and anticholinergic medication along with underlying and potentially complicating conditions such as constipation and UTIs. Behavioural modification, mostly referred to as urotherapy, is a term which covers all non-pharmacological and non-surgical treatment modalities. It includes standardisation of fluid intake, bowel management; timed voiding

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and basic relaxed voiding education. The child and family are educated about normal bladder function and responses to urgency. Voiding regimens are instituted and UTIs and any constipation are treated. Treatment is aimed at optimising bladder emptying and inducing full relaxation of the urinary sphincter or pelvic floor prior to and during voiding. Strategies to achieve these goals include: 1. 2.

Information and demystification, which includes explanation about normal LUT function and how a particular child deviates from normal function. Instructions about what to do about the problem: • Regular voiding habits, sound voiding posture, pelvic floor awareness and training to relax pelvic floor and avoiding holding manoeuvres. • Lifestyle advice, regarding fluid intake, prevention of constipation, etc. • Registration of symptoms and voiding habits using bladder diaries or frequency-volume charts. • Support and encouragement via regular follow-up by the caregiver.

Recurrent UTIs and constipation should also be treated and prevented during the treatment period. In case of combined BBD it is advised to treat the bowel dysfunction first [512] as LUTS may disappear after successful management of bowel dysfunction. Addition of other strategies, as below, may be needed: • • • •

Pelvic floor muscle awareness practices with repeated sessions of biofeedback visualisation of uroflow curves and/or pelvic floor activity and relaxation. Clean intermittent self-catheterisation for large PVR volumes of urine. Antimuscarinic drug therapy if detrusor overactivity is present. If the bladder neck is associated with increased resistance to voiding, α-blocker drugs may be introduced.

Treatment efficacy can be evaluated by improvement in bladder emptying and resolution of associated symptoms. Controlled studies of the various interventions are needed. As with detrusor overactivity, the natural history of untreated dysfunctional voiding is not well delineated and optimum duration of therapy is poorly described. A high success rate has been described for urotherapy programmes, independent of the components of the programme. However, the evidence level is low as most studies of urotherapy programmes are retrospective and non-controlled [533]. A recent Cochrane analysis found very little evidence that can help to make evidene-based treatment decisions [534]. 3.10.3.1 Specific interventions As well as urotherapy, there are some specific interventions, including physiotherapy (e.g. pelvic floor exercises), biofeedback, alarm therapy and neuromodulation. Although good results with these treatment modalities have been reported, the level of evidence remains low, since only a few RCTs were published [535541]. A systematic review reports that biofeedback is an effective, non-invasive method of treating dysfunctional voiding, and approximately 80% of children benefited from this treatment. However, most reports were of low level of evidence and studies of more solid design such as RCTs should be conducted [542]. A more recently published multicentre controlled trial of cognitive treatment, placebo, oxybutynin and bladder and pelvic floor training did not report better results with oxybutynin and pelvic floor training compared to standard urotherapy [532] (LE: 1b). Two RCTs on underactive bladder without neurophatic disease have recently been published. Transcutaneous interferential electrical stimulation and animated biofeedback with pelvic floor exercise have been shown to be effective [543, 544]. In some cases, pharmacotherapy may be added. Some studies on orthosympathicomimetics have been published with a low level of evidence [545]. Overactive bladder is common in the paediatric population. Although a stepwise approach starting with behavioural therapy is advised, antimuscarinic agents remain the mainstay of medical treatment for OAB. Oxybutynin is the most commonly used antimuscarinic in the paediatric population. The response to antimuscarinics varies and many children experience serious side effects. Although there have been reports about the use of tolterodine, fesoterodine, trospium, propiverine, and solifenacin in children, to date, most of them are off-label depending on age and national regulations. A few RCTs have been published, one

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on tolterodine showed safety but not efficacy [546], while another on propiverine showed both safety and efficacy [547] (LE:1). The recent study on solifenacin showed its efficacy with side effects like constipation and electrocardiogram changes [548]. The difference in results is probably due to study design. Despite the low level of evidence for the use of anticholinergics and antimuscarinics, their use is recommended because of the large number of studies reporting a positive effect on OAB symptoms. Although α-blocking agents are used occasionally, an RCT showed no benefit [549]. Botulinum toxin injection seems promising, but can only be used off-label [550]. A meta-analysis reports that neuromodulation therapy may lead to better partial improvement of nonneurogenic OAB; however, it may not render a definitive complete response. Office-based neuromodulation seems more efficacious than self-administered neuromodulation [551]. These new treatment modalities can only be recommended for standard therapy-resistant cases [552]. Despite early successful treatment, there is evidence that there is a high recurrence rate of symptoms in the long term which necessitates long-term followup [553]. In addition, many patients may present later in adulthood with different forms of LUTD [554]. 3.10.4

Summary of evidence and recommendations for the management of day-time lower urinary tract conditions

Summary of evidence The term ‘bladder bowel dysfunction’ should be used rather than ‘dysfunctional elimination syndrome and voiding dysfunction’. Day-time LUTS has a high prevalence (1% to 20%).

Recommendations Use two day voiding diaries and/or structured questionnaires for objective evaluation of symptoms, voiding drinking habits and response to treatment. Use a stepwise approach, starting with the least invasive treatment in managing day-time lower urinary tract dysfunction in children. Initially offer urotherapy involving bladder rehabilitation and bowel management. If bladder bowel dysfunction is present, treat bowel dysfunction first, before treating the lower urinary tract condition. Use pharmacotherapy (mainly antispasmodics and anticholinergics) as second line therapy in overactive bladder. Use antibiotic prophylaxis if there are recurrent infections. Re-evaluate in case of treatment failure; this may consist of (video) urodynamics MRI of lumbosacral spine and other diagnostic modalities, guiding to off-label treatment which should only be offered in highly experienced centres.

3.11

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Monosymptomatic nocturnal enuresis - bedwetting

3.11.1 Epidemiology, aetiology and pathophysiology Monosymptomatic nocturnal enuresis, also known as bedwetting, is defined as an intermittent nocturnal incontinence. It is a relatively frequent symptom in children, 5-10% at seven years of age and 1–2% in adolescents. With a spontaneous yearly resolution rate of 15% (at any age), it is considered as a relatively benign condition [530, 555]. Seven out of 100 seven-year-old bedwetting children will continue to wet their bed into adulthood. Nocturnal enuresis is considered primary when a child has not yet had a prolonged period of being dry (six months). The term “secondary nocturnal enuresis” is used when a child or adult begins wetting again after having stayed dry. Non-monosymptomatic nocturnal enuresis is defined as the condition of nocturnal enuresis in association with day-time lower urinary tracts symptoms (LUTS, recurrent UTIs and/or bowel dysfunction) [555, 556]. Nocturnal enuresis has significant secondary stressful, emotional and social consequences for the child and their caregivers. Therefore treatment is advised from the age of six to seven years onwards considering mental status, family expectations, social issues and cultural background. There is a clear hereditary factor in nocturnal enuresis. If none of the parents or their immediate relatives has suffered from bedwetting, the child has a 15% chance of wetting its bed. If one of the parents, or their immediate relatives have suffered from bedwetting, the chance of bedwetting increases to 44%, and if both parents have a positive history the chance increases to 77%. However, from a genetic point of view,

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enuresis is a complex and heterogeneous disorder. Loci have been described on chromosomes 12, 13 and 22 [556]. There is also a gender difference: two boys to one girl at any age. High arousal threshold is the most important pathophysiological factor; the child does not wake up when the bladder is full. In addition to the high arousal threshold, there needs to be an imbalance between night-time urine output and night-time bladder capacity and activity [530, 555, 556]. Recently, attention has been given to the chronobiology of micturition in which the existence of a circadian clock in kidney, brain and bladder is postulated [557] (LE: 1). A high incidence of comorbidity and correlation between nocturnal urine production and sleep disordered breathing, such as obstructive sleep apnoea, has been found and investigated. Symptoms such as habitual snoring, apnoeas, excessive sweating at night and mouth breathing in the patient history or via sleep questionnaires can lead to the diagnosis of adenotonsillar hypertrophy. 3.11.2 Diagnostic evaluation The diagnosis is mainly obtained by history-taking. Focused questions to differentiate monosymptomatic vs. non-monosymptomatic, primary vs. secondary, comorbid factors such as behavioural or psychological problems and sleep disorder breathing, should be asked. In addition, a two day complete voiding and drinking diary, which records day-time bladder function and drinking habits will further exclude comorbid factors such as LUTS and polydipsia. The night-time urine production should be registered by weighing the night-time diapers in the morning and adding the first morning voided volume [558]. The night-time urine production should be recorded over (at least) a two week period to diagnose an eventual differentiation between a high night-time production (more than 130% of the age expected bladder capacity) vs. a night-time OAB. A physical examination should be performed with special attention to the external genitalia and surrounding skin as well as to the condition of the clothes (wet underwear or encopresis). Urine analysis is indicated if there is a sudden onset of bedwetting, a suspicion or history of UTIs, or inexplicable polydipsia. A uroflowmetry and US is indicated only if there is a history of previous urethral or bladder surgery, straining while voiding, interrupted voiding, an abnormal weak or strong stream, or a prolonged voiding time. If the comorbid factor of possible sleep disordered breathing occurs, a referral to an ear-nose-throat (ENT) specialist should be advised. If the comorbid factor is developmental, attention or learning difficulties, family problems, parental distress and possible punishment of the child, a referral to a psychologist should be advised and followed-up. 3.11.3 Management Before introducing any form of possible treatment, it is of utmost importance to explain the bedwetting condition to the child and the caregivers in order to demystify the problem. 3.11.3.1 Supportive treatment measures Initially, supportive measures including normal and regular eating and drinking habits should be reviewed, stressing normal fluid intake during the day and reducing fluid intake in the hours before sleep. Keeping a chart depicting wet and dry nights, also called as basic bladder advice, has not been shown to be successful in the early treatment of nocturnal enuresis [559] (LE: 1a). 3.11.3.2 Conservative “wait and see” approach If the child and its family is unable to comply with a treatment, if the treatment options are not possible for the family situation, and if there is no social pressure, a “wait and see” approach can be chosen. However, in this approach, it is important to emphasise the fact that the child should wear diapers at night to ensure a normal quality of sleep. 3.11.3.3 Nocturnal enuresis wetting alarm treatment The nocturnal alarm treatment is the use of a device that is activated by getting wet. The goal is that the child wakes up by the alarm, which can be acoustic or tactile, either by itself or with the help of a caregiver. The method of action is to repeat the awakening and therefore change the high arousal to a low arousal threshold, specifically when a status of full bladder is reached. It is of utmost importance that the child is collaborating. Initial success rates of 80% are realistic, with low relapse rates, especially when night-time diuresis does not exceed age-expected bladder capacity [560]. Regular follow-up will improve the success.

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3.11.3.4 Medical therapy In the case of high night-time diuresis, success rates of 70% can be obtained with desmopressin (DDAVP), either as tablets (200-400 μg), or as sublingual DDAVP oral lyophilisate (120-240 μg). A nasal spray is no longer recommended due to the increased risk of overdose [561, 562] (LE: 1). Relapse rates can be high after DDAVP discontinuation [555], however recently, structured withdrawal has shown lower relapse rates [563] (LE: 1). In the event of desmopressin-resistant treatment for nocturnal enuresis or if a suspicion exists for night-time OAB, combination with antispasmodics or anticholinergics is safe and efficient [558]. Imipramine, which has been popular for treatment of enuresis, achieves only a moderate response rate of 50% and has a high relapse rate. Furthermore, cardiotoxicity and death from overdose are described, its use should therefore be discouraged as the first-line therapy [564] (LE: 1). Figure 6 presents stepwise assessment and management options for nocturnal enuresis. Although several forms of neuromodulation and acupuncture have been investigated for nocturnal enuresis treatment, present data precludes their use because of its inefficiency, or at least no additional benefit. Figure 6: A stepwise assessment and management options for nocturnal enuresis Child ≥ 5 years nocturnal enuresis

Detailed questions for day-time symptoms

Physical exam and urinanalysis

2 days day-time voiding and drinking diary

2 weeks night-time urine production recording (= weight night-time diapers + morning first voided volume)

Upon indication • Urine microscopy • Uroflow metry • Ultrasound • ENT referral • Psychologist referral

Supportive measures (not a treatment) (max 4 weeks) • Normal and regular drinking habits • Regular voiding and bowel habits • Monitor night-time production (weight diapers)

Child + caregivers seek a treatment

Nocturnal enuresis wetting alarm treatment with regular follow-up

desmopressin +/- anticholinergics

If no improvement (< 4 weeks) OR Lack of compliance + Re-evaluate

ENT = ear, nose and throat.

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3.11.4

Summary of evidence and recommendations for the management of monosymptomatic enuresis

Summary of evidence Chronobiology of micturition, in which the existence of a circadian clock has been proven in kidney, brain and bladder, and disturbances in this chronobiology play a major role in the pathophysiology of enuresis.

Recommendations Do not treat children less than five years of age in whom spontaneous cure is likely, but inform the family about the involuntary nature, the high incidence of spontaneous resolution and the fact that punishment will not help to improve the condition. Use voiding diaries or questionnaires to exclude day-time symptoms. Perform a urine test to exclude the presence of infection or potential causes such as diabetes insipidus. Offer supportive measures in conjunction with other treatment modalities, of which pharmacological and alarm treatment are the two most important. Offer desmopressin in proven night-time polyuria. Offer alarm treatment in motivated and compliant families.

3.12

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Management of neurogenic bladder

3.12.1 Epidemiology, aetiology and pathophysiology Neurogenic detrusor-sphincter dysfunction (NDSD) can develop as a result of a lesion at any level in the nervous system. This condition contributes to various forms of LUTD, which may lead to incontinence, UTIs, VUR, and ultimately to renal scarring and renal failure requiring dialysis and/or transplantation. Conservative treatment starting in the first year of life is the first choice, however, surgery may be required at a later stage to establish adequate bladder storage, continence and drainage later on [565-567]. The main goals of treatment concerning the urinary tract are prevention of UTI’s, urinary tract deterioration, achievement of continence at an appropriate age and promoting as good a QoL as possible. With regard to the associated bowel dysfunction, stool continence, with evacuation at a social acceptable moment, is another goal as well as education and treatment of disturbance in sexual function. Due to the increased risk of development of latex allergy, latex-free products (e.g., gloves, catheters etc.) should be used from the very beginning whenever possible [568]. Neurogenic bladder in children with myelodysplasia presents with various patterns of Detrusor-SphincterDyssynergia with a wide range of severity [569]. About 12% of neonates with myelodysplasia have no signs of neuro-urological dysfunction at birth [570]. Newborns with myelodysplasia and initially normal urodynamic studies are at risk for neurological deterioration secondary to spinal cord tethering, especially during the first six years of life. Close follow-up of these children is important for the early diagnosis and timely surgical correction of tethered spinal cord, and for the prevention of progressive urinary tract deterioration [570]. At birth, the majority of patients have normal UUTs, but up to 60% develop upper tract deterioration due to bladder changes, UTI and /or VUR, if not treated properly [571-574]. Even today in a contemporary series around 50% of the patients are incontinent and 15% have an impaired renal function at the age of 29 years [575]. A recent systematic review concerning the outcome of adult meningomyelocele patients demonstrated that around 37% (8-85%) are continent, 25% have some degree of renal damage and 1.3% end stage renal failure [576]. The term “continence” is used differently in the reports, and the definition of “always dry” was used in only a quarter of the reports [577]. The most common presentation at birth is myelodysplasia. The incidence of neural tube defects in Europe is 9.1 per 10,000 births and has not decreased in recent years, despite longstanding recommendations concerning folic acid supplementations [578]. The term myelodysplasia includes a group of developmental anomalies that result from defects in neural tube closure. Lesions include spina bifida aperta and occulta, meningocele, lipomyelomeningocele, or myelomeningocele. Myelomeningocele is by far the most common defect seen and the most detrimental. With antenatal screening spina bifida can be diagnosed before birth with the possibility of intrauterine closure of the defect [579, 580]. Traumatic and neoplastic spinal lesions of the cord are less frequent in children, but can also cause severe urological problems. Other congenital malformations or acquired diseases can cause a neurogenic bladder, such as total or partial sacral agenesis which can be part

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of the caudal regression syndrome [581]. In any child presenting with anorectal malformation (ARM) and cloacal malformations, the development of a neurogenic bladder is possible [582]. Patients with cerebral palsy may also present with varying degrees of voiding dysfunction, usually in the form of uninhibited bladder contractions (often due to spasticity of the pelvic floor and sphincter complex) and wetting. Finally, a “non-neurogenic neurogenic” bladder, such as Hinman or Ochoa syndrome, has been described, in which no neurogenic anomaly can be found, but severe bladder dysfunction as seen in neurogenic bladders is present [583, 584]. 3.12.2 Classification systems As bladder sphincter dysfunction is poorly correlated with the type and spinal level of the neurological lesion, urodynamic and functional classifications are much more practical for defining LUT pathology and planning treatment in children. The bladder and sphincter are two units working in harmony to act as a single functional unit. In patients with a neurogenic disorder, the storage and emptying phase of the bladder function can be disturbed. The bladder and sphincter may function either overactive or underactive and present in four different combinations. This classification system is based on urodynamic findings [585-587]: • • • •

Overactive sphincter and overactive bladder. Overactive sphincter and underactive bladder. Underactive sphincter and overactive bladder. Underactive sphincter and underactive bladder.

3.12.3 Diagnostic evaluation Today several guidelines and timetables are used [588-590]. The Panel advocate proactive management in children with spinal dysraphism. In those with a safe bladder during the first urodynamic investigation, the next urodynamic investigation can be delayed until one year of age. 3.12.3.1 History and clinical evaluation History should include questions on clean intermittent catheterisation (CIC) frequency, urine leakage, bladder capacity, UTI, medication, bowel function as well as changes of neurological status. A thorough clinical evaluation is mandatory including the external genitalia and the back. A two day diary, recording drinking volume and times as well as CIC intervals, bladder volume and leakage can provide additional information about the efficacy of the treatment. 3.12.3.2 Laboratory and urinalysis After the first week of life, the plasma creatinine level should be obtained, later in life; the cystatin level is more accurate [591, 592]. If there is any sign of decreased renal function, physicians should be encouraged to optimise the treatment as much as possible. The criteria for urine analysis are the same as for UTI (refer to Chapter 3.9). However, it is much easier for caregivers or patients to obtain catheter urine in patients who are on CIC. They can also perform a dip stick analysis to screen for UTI at home. (For relevance see Section 3.12.4.5) 3.12.3.3 Ultrasound At birth, US of the kidneys and bladder should be performed and then repeated at least annually. If there are any clinical changes in between, another US should be performed. Dilatation of the UUT should be reported according to the classification system of the Society of Foetal Urology [593], including the measurement of the caliceal dilatation and anterior posterior diameter of the renal pelvis. Residual urine and bladder wall thickness should also be mentioned. A dilated ureter behind the bladder should be recorded. Bladder wall thickness has been shown not to be predictive of high pressures in the bladder during voiding and storage and cannot be used as a non-invasive tool to judge the risk for the UUT [594]. 3.12.3.4 Urodynamic studies/videourodynamic Urodynamic studies (UD) are one of the most important diagnostic tools in patients with neurogenic bladders. In newborns with spina bifida aperta (failure of mesodermal in-growth over the developing spinal canal results in an open lesion most commonly seen in the lumbosacral area including an incomplete closure of the vertebral column and not covered by skin), the first UD should be performed after the phase of the spinal shock after closure, usually between the second and third months of life [595]. Especially in newborns, performing and interpretation of UD may be difficult, as no normal values exist. After that it should be repeated annually, depending on the clinical situation. During and after puberty bladder capacity, maximum detrusor pressure and detrusor leak point pressure increase significantly [596]. Therefore, during this time, a careful follow-up is mandatory.

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3.12.3.4.1 Preparation before urodynamic studies Before any UD a urine analysis should be undertaken. The first assessment should be done under antibiotic prophylaxis. A Cochrane analysis of nine randomised controlled trials showed, that the administration of prophylactic antibiotics compared to placebo reduced the risk of significant bacteriuria from 12% to 4% after UD studies. However, this was without significant difference for symptomatic UTI (20% vs. 28%), fever or dysuria [597]. If there is a significant bacteriuria, antibacterial treatment should be discussed; especially in older patients a single shot may be sufficient [598]. Generally UD-parameters should include: • the bladder cystometric capacity; • the intravesical filling pressure; • detrusor compliance; • the intravesical pressure at the moment of voiding or leakage; • the presence or absence of overactive detrusor; • the competence of the internal and external sphincter; • the degree of synergy of the detrusor and sphincter during voiding; • the PVR urine volume. In infants, information on detrusor filling pressure and the pressure and bladder volume at which the child voids or leaks can be obtained [595]. Detrusor leak point pressure is more accurate than abdominal leak point pressure, but keeping the rectal probe in an infant in place can be challenging [595]. Addition of fluoroscopy (video-urodynamic study) will provide information about presence of VUR, at what pressures VUR starts and the configuration of the bladder neck during filling and leakage or voiding. 3.12.3.4.2 Uroflowmetry Unlike in children with non-neurogenic voiding dysfunction, uroflowmetry can rarely be used since most affected patients do not void spontaneously. In those with cerebral palsy, non-neurogenic-neurogenic bladder or other neurological conditions allowing active voiding it may be a practical tool. It provides an objective way of assessing the efficiency of voiding, while recording of pelvic floor activity with electromyography (EMG) can be used to evaluate synergy between detrusor and the sphincter. The PVR urine is measured by US. The main limitation of uroflowmetry is a compliant child to follow instructions [599-602]. 3.12.3.5 Urodynamic studies The standards of the ICCS should be applied to UDs in patients with neurogenic bladders and accordingly reported [522, 585]. Natural fill UD in children with neurogenic bladder detects more overactivity compared with diagnoses delivered by conventional UD [603, 604]. It may be an option in patients where the findings in the normal UD are inconsistent with clinical symptoms and other clinical findings [604]. 3.12.3.6 Voiding cystourethrogram If video-urodynamic equipment is not available, a VCUG with UD is an alternative to confirm or exclude VUR and visualise the LUT including the urethra. 3.12.3.7 Renal scan DMSA (Technetium Dimercapto-Succinic Acid) Renal scan is the gold standard to evaluate renal parenchyma. In contemporary series, renal scars can be detected in up to 46% as patients get older [605-607]. A positive DMSA-Scan correlates well with hypertension in adulthood, whereas US has a poor correlation with renal scars [607]. Therefore, a DMSA scan as a baseline evaluation in the first year of life is recommended. 3.12.4 Management The medical care of children with neurogenic bladder requires an on-going multidisciplinary approach. There is some controversy about optimal timing of the management; proactive vs. expectant management [565-567]. Even with a close expectant management e.g. in one series 11 out of 60 need augmentation within a followup of 16 years and 7 out of 58 had a decrease in total renal function, which was severe in two [608]. During the treatment it should be also taken into account with spina bifida patients, that QoL is related to urinary incontinence independent from the type and level of spinal dysraphism and the presence or absence of a liquor shunt [609]. Foetal open and endoscopic surgery for meningomyelocele are performed to close the defect as early as possible to reduce the neurological, orthopaedic and urological problems [610]. In the MOMS-Trail, Brooks et al. found no difference between those closed in utero vs. those closed after birth concerning the need for CIC

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[580], but less trabeculation was found in the prenatal surgery group. Mean gestation age (28.3 vs. 35.2) seems to have no initial impact on bladder function in the first few years of life [611]. Despite some promising reports [611-614], caregivers need to be aware of the high risk of developing a neurogenic bladder as demonstrated by a Brazilian group [615]. Regular and close follow-up examinations including UD are indicated in all these patients. 3.12.4.1 Early management with intermittent catheterisation Starting intermittent catheterisation (IC) soon after birth and closure of the defect by the neurosurgeon in all infants has shown to decrease renal complications and the need for later augmentation [616-618]. In infants without any clear sign of outlet obstruction, this may be delayed but only in very selected cases. These infants should be monitored very closely for UTIs and changes of the urinary tract with US and UD. The early initiation of IC in the newborn period makes it easier for caregivers to master the procedure and for children to accept it, as they grow older [619, 620]. A Cochrane review as well as some recent studies showed, that there is a lack of evidence to state that the incidence of UTI is affected by use of sterile or clean technique, coated or uncoated catheters, single (sterile) or multiple use (clean) catheters, self-catheterisation or catheterisation by others, or by any other strategy [621-624]. Looking at the microbiological milieu of the catheter, there was a trend for reduced recovery of potentially pathogenic bacteria with the use of hydrophilic catheters. Also, a trend for a higher patient satisfaction with the use of hydrophilic catheters was seen [625]. Based on the current data, it is not possible to state that one catheter type, technique or strategy is better than another. 3.12.4.2 Medical therapy Antimuscarinic/anticholinergic medication reduces/prevents detrusor overactivity and lowers intravesical pressure [626, 627]. Effects and side effects depend on the distribution of the M1-M5 receptors [628]. In the bladder, the subtype M2 and M3 are present [627, 629]. Oxybutynin is the most frequently used in children with neurogenic bladder with a success rate of up to 93% [630, 631]. Dose-dependent side-effects (such as dry mouth, facial flushing, blurred vision heat intolerance etc.) limit its use. Intravesical administration has a significant higher bioavailability due to the circumvention of the intestinal first pass metabolism, as well as possible local influence on C-fiber-related activity and can be responsible for different clinical effect [632, 633]. Intravesical administration should be considered in patients with severe side-effects, as long-term results demonstrated that it was well-tolerated and effective [634, 635]. The transdermal administration leads also to a substantial lower ratio of N-desethyloxybutynin to oxybutynin plasma levels, however, there are treatmentrelated skin reactions in 12 out of 41 patients [636]. There are some concerns about central anticholinergic adverse effects associated with oxybutynin [637, 638]. A double blinded cross-over trial, as well as a case control study, showed no deleterious effect on children’s attention and memory [639, 640]. Tolterodine, solifenacin, trospium chloride and propiverine and their combinations can be also used in children [641-647]. The oral dosage for oxybutynin is up to 0.2 mg/kg/every 8 hours [627] given three times daily. The intravesical dosage can be up to 0.7 mg/kg/daily and transdermal 1.3-3.9 mg/daily. The dosage of the other drugs is: Tolterodine 0.5 – 4 mg/day divided in two doses, Solifenacin 1.25 up to 10 mg per day (single dose), Propiverin 0.8 mg/kg/day divided in two dosages and trospium chloride up to 3 times 15 mg starting with 3 times 5 mg. Except for oxybutynin, all other anticholinergic drugs are off-label use, which should be explained to the caregivers. Early prophylactic treatment with anticholinergics showed a lower rate of renal deterioration as well as a lower rate of progression to bladder augmentation [616, 618, 648]. Beta-3 agonists like mirabegron may also be an alternative agent and may be effective in patients with neurogenic bladders. To date, there is almost no experience with this drug [649], therefore no recommendation can be made. Alpha-adrenergic antagonists may facilitate emptying in children with neurogenic bladder [650]. Doxazosin with an initial dose of 0.5 to 1.0 mg or tamsulosin hydrochloride in a medium (0.0002-0.0004 mg/kg/ day) or high dose (0.0004-0,0008 mg/kg/day) has been given to children with neurogenic bladders [650-652]. It was well tolerated but not effective at least in one study [651]. Botulinum toxin A injections: In neurogenic bladders that are refractory to anticholinergics, the off-label use of suburothelial or intramuscular injection of onabotulinum toxin A into the detrusor muscle is a treatment option [653, 654]. In children, continence could be achieved in 32-100% of patients, a decrease in maximum detrusor pressure of 32% to 54%, an increase of maximum cystometric capacity from 27% to 162%, and an improvement in bladder compliance of 28%-176% [653]. Onabotulinum toxin A seems to be more effective in bladders with obvious detrusor muscle over-activity, whereas non-compliant bladders without obvious contractions are unlikely to respond [655, 656]. Also, the injections into the trigone seems to be save in regard of reflux and upper tract damage; if it has some benefit is not further investigated [657]. The most commonly used dose of onabotulinum toxin A is 10 to 12 U/kg with a maximum dose between 200 U and 360 U [653]. However, in one study, 5 U/kg were used with comparable results [658]. To date, no randomised dose titration study has been published in children. The optimal dose in children as well

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as the time point when to inject which child is still unclear. Onabotolinum toxin A can be effective between three to twelve (0-25) months and repeated injections are effective up to ten years in one study [654, 659, 660]. Urethral sphincter onabotulinum toxin A injection has been shown to be effective in decreasing urethral resistance and improve voiding. The evidence is still too low to recommend its routine use in decreasing outlet resistance, but it could be considered as an alternative in refractory cases [661, 662]. Neuromodulation Intravesical electrical stimulation of the bladder [663-665], sacral nerve stimulation [666, 667] and transcutaneous neuromodulation [668] are still experimental and cannot be recommended outside of clinical trials. The same is true for the intradural somatic-to-autonomic nerve anastomosis [669, 670]. Urethral Dilatation The aim is to lower the pop-off pressure by lowering the detrusor leak-point pressure by dilatation of the external sphincter under general anaesthesia up to 36 Charr. Some studies showed, that especially in females, the procedure is safe and in selected patients, effective [671-673]. Vesicostomy Vesicostomy - preferably a Blocksom stoma [674] - is an option to reduce bladder pressure in children/ newborns, if the caregivers are incompliant with IC and/or IC through the urethra is extremely difficult or impossible [675]. Especially in the young infant with severe upper tract dilatation or infections, a vesicostomy should be considered. Drawbacks are the difficulty fitting and maintaining a collecting appliance in older patients. A cystostomy button may be an alternative, with a complication rate (mostly UTI) of up to 34% within a mean follow-up of 37 months [676]. 3.12.4.3 Management of faecal incontinence Children with neurogenic bladder usually have also a neurogenic bowel function. Faecal incontinence may have an even greater impact on QoL, as the odour can be a reason for social isolation. The aim of each treatment is to obtain a smooth, regular bowel emptying and to achieve continence and impendence. The regime should be tailored to the patient’s need, which may change over time. Beside a diet with small portioned fibre food and adequate fluid intake to keep a good fluid balance [627], follow-up options should be offered to the patients and caregivers. In the beginning, faecal incontinence is managed most commonly with mild laxatives, such as mineral oil, combined with enemas to facilitate removal of bowel contents. To enable the child to defecate once a day at a given time, rectal suppositories as well as digital stimulation by parents or caregivers can be used. Today, transanal irrigation is one of the most important treatments for patients with neurogenic bowel incontinence. Regular irrigations significantly reduce the risk for faecal incontinence and may have a positive effect on the sphincter tonus as well as the rectal volume [677]. The risk of irrigation induced perforation of the bowel is estimated as one per 50,000 [678]. During childhood, most children depend on the help of the caregivers. Later in some patients, transanal irrigation becomes difficult or impossible due to anatomic or social circumstances. In these patients antegrade irrigation using a MACE-stoma (Malone Antegrade Continence Enema) is an option, which can also be placed in the left abdomen [679, 680]. In a long-term study of 105 patients, 69% had successful bowel management. They were started on normal saline, but were switched to GoLYTELY (PEG-3350 and electrolyte solution). Additives (biscodyl, glycerin etc.) were needed in 34% of patients. Stomal complications occurred in 63% (infection, leakage, and stenosis) of patients, 33% required surgical revision and 6% eventually required diverting ostomies [681]. In addition, patients need to be informed, that the antegrade irrigation is also time consuming taking at least 20-60 minutes.. 3.12.4.4 Urinary tract infection Urinary tract infections are common in children with neurogenic bladders. However, there is no consensus in most European centres, for prevention, diagnosing and treating UTIs in children with neurogenic bladders performing CIC [682]. Although bacteriuria is seen in more than half of children on CIC, patients who are asymptomatic do not need treatment [683, 684]. Continuous antibiotic prophylaxis (CAP) creates more bacterial resistance as demonstrated by a randomised study. Those that stopped the prophylaxis had reduced bacterial resistance, however, 38 out of 88 started antibiotic prophylaxis again due to recurrent UTIs or the caregivers request [685]. A cohort study with 20 patients confirmed these findings. Continuous antibiotic prophylaxix was not protective against the development of symptomatic UTIs and new renal scarring, but increased the risk of bacterial resistance [686]. A randomised study in 20 children showed that cranberry capsules significantly reduced the UTI-rate as well as the rate of bacteriuria [687]. If VUR is present, prophylactic antibiotics should be started when patients experience recurrent UTIs [688, 689].

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3.12.4.4.1 Urinary tract infection and clean intermittent catherisation The incidence of asymptomatic bacteriuria ranges between 42%-76% [619, 627, 690]. A cross-over study in 40 children with neurogenic bladder demonstrated, that the reuse of CIC-catheters for up to three weeks compared to one week increased the prevalence of bacteriuria from 34% to 74% (it was 60% at the start of the study). During the study-period of eighteen weeks, none of the patients developed a febrile UTI [691]. There is no medical benefit in performing CAP in children with neurogenic bladder, who perform CIC [627]. In those with recurrent UTI, intravesical instillation of gentamycin may be an option [692, 693]. Reflux Secondary reflux in patients with neurogenic bladder increases the risk for pyelonephritis. The treatment is primary related to bladder function including anticholinergic therapy, CIC and may be later augmentation [694]. Those with early and post-therapy persistent reflux during videourodynamic studies at low pressure have a higher risk of pyelonephritis [695]. Patients with a high-grade reflux before augmentation have a higher risk of persistent symptomatic reflux after the enterocystoplasty [696]. Therefore simultaneous ureteral re-implantation in high-grade symptomatic reflux especially in those with low-pressure high-grade reflux should be discussed with the patient/caregivers. Endoscopic treatment has a failure rate of up to 75% after a median follow-up of 4.5 years [697] which is in contrast to the open techniques with a higher success rate, but may have an increased risk of inducing obstruction [698]. 3.12.4.5 Sexuality Sexuality, while not an issue in childhood, becomes progressively more important as the patient gets older. This issue has historically been overlooked in individuals with myelodysplasia. However, patients with myelodysplasia do have sexual encounters [699]. The prevalence of precocious puberty is higher in girls with meningomyelocele [700]. Studies indicate that at least 15-20% of males are capable of fathering children and 70% of females can conceive and carry a pregnancy to term. It is therefore important to counsel patients about sexual development in early adolescence. Women seem to be more sexually active than men in some studies from the USA and the Netherlands [699, 701]; in an Italian study men were more active [701]. The level of the lesion was the main predictor to be sexually active [702, 703]. Erectile function can be improved by sildenafil in up to 80% of the male patients [704, 705]. Neurosurgical anastomosis between the inguinal nerve and the dorsal penile nerve in patients with a lesion below L3 and disturbed sensation is still to be considered as an experimental treatment [701, 706]. Only 17% to one third of the patients talk to their doctors about sexuality, 25–68% were informed by their doctors about reproductive function [699]. Therefore, early discussion about sexuality in the adolescent is recommended and should be promoted by the paediatric urologist taking care of these patients. 3.12.4.6 Bladder augmentation In patients where conservative treatment including onabotulinum toxin A (for indication see 3.12.4.3) fails to keep a low-pressure reservoir with a good capacity and compliance, bladder augmentation should be offered. For augmentation, ileal and colonic segments can be used [707]. Gastric segments are rarely used due to its associated complications like the haematuria-dysuria syndrome as well as secondary malignancies, which arise earlier than with other intestinal segments [708-711]. Enterocystoplasty increases bladder capacity, reduces storage pressure and can improve UUT drainage [712]. A good socially acceptable continence rate can be achieved with or without additional bladder outlet procedures [713]. In those, who are not able to perform CIC through the urethra, a continent cutaneous channel should be offered. Surgical complications and revision rate in this group of patients is high. The 30-day all over event rate in the American College of Surgeons’ National Surgical Quality Database is approximately 30% (23-33%) with a re-operation rate in this short time period of 13% [714, 715]. In these patients with long-life expectancy the complication rate clearly increases with the follow-up period [714-717]. The ten-year cumulative complication incidence from the Paediatric Health Information System showed a rate of bladder rupture in up to 6.4%, small bowel obstruction in up to 10.3%, bladder stones in 36%, pyelonephritis in more than a third of the patients and a re-augmentation rate of up to 13% [718]. Bladder perforation, as one of the worst complications, occurs in 6-13% [719]. The rate of VP-shunt infections after gastrointestinal and urological procedures ranges between 0-22%. In a recent study, bowel preparation seems not to have a significant influence on the infection rate (10.5% vs. 8.3%) [720]. Not only surgical complications must be considered; also metabolic complications and consequences after incorporating bowel segments have to be taken into account, such as imbalance of the acid base balance, decrease in vitamin B12 levels and loss of bone density. Stool frequency can increase as well as diarrhoea after exclusion of bowel segments [721] and last, but not least, these patients have a lifelong increased risk to develop secondary malignancies [722, 723]. Therefore, a lifelong follow-up of these patients is required including physical examination, US, blood gas analysis, (pH and base excess), renal function and

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vitamin B12 if Ileum is used. Endoscopic evaluation starting ten years after augmentation is not cost-effective [724, 725], but may prevent some advanced cancer. Woodhouse et al. do not recommend cystoscopy within the first fifteen years after surgery [726]. The real value of annual cystoscopic evaluation has not been proven by any study. Urodynamic studies after bladder augmentation are only indicated, if upper tract dilatation and/or incontinence after the operation has not improved [727]. Adverse effects of intestinal cystoplasties can be avoided by the use of ureterocystoplasty. The combination of a small contracted bladder, associated with a severe dilation of the ureter of a non-functioning kidney is quite rare. The technique was first described in 1973 by Eckstein [728]; the success rate depends on patient selection and the re-augmentation rate can reach 73% [729, 730]. Auto-augmentation with partial detrusorectomy or detrusormyotomy creating a diverticulum avoids metabolic complications with the use of intestinal segments. The reports are conflicting, therefore, it may be used in selected cases [731-734]. For a successful outcome, a pre-operative bladder capacity of 75-80% of the expected volume seems necessary [735, 736]. Seromuscular cystoplasty has also not proven to be as successful as standard augmentation with intestine [737]. Tissue engineering, even if successful in vitro and some animal models, does not reach the results by using intestinal segments with a higher complication rate [738, 739]. Therefore, these alternatives for bladder augmentation should be considered as experimental and should be used only in controlled trials. 3.12.4.7 Bladder outlet procedures No available medical treatment has been validated to increase bladder outlet resistance. Alpha-adrenergic receptor stimulation of the bladder neck has not been effective [740-745]. Using fascial slings with autologous fascial strip or artificial material a continence rate between 40-100% can be achieved. In most cases this is achieved in combination with bladder augmentation [746, 747]. Catheterising through a reconstructed bladder neck or a urethra compressed by a sling may not be easy; many surgeons prefer to combine this approach with a catheterisable channel [565]. In contrast to the autologous slings, artificial slings in girls with CIC through the urethra have a high complication rate [748]. In males, it may be an option [749], however as long as long-term results are missing, this method has to be classified as experimental and should only be carried out in studies. Artificial urinary sphincters were introduced by Scott in 1973 [750]. The continence rates in the literature in selected patients can be up to 85% [751-754]. Post-pubertal patients, who can void voluntary are good candidates, if they are manually dexterous. In very selected patients, CIC through the sphincter in an augmented bladder is possible [755]. The erosion rate can be up to 29% and the revision rate up to 100% depending on the follow-up time [756]. Patients, who underwent a bladder neck procedure only, have a chance of > 30% for an augmentation later on; half of them developed new upper tract damage in that time [757, 758]. In patients with a good bladder capacity and bladder compliance without an indication for bladder augmentation, there is a risk of postoperative changes of the bladder function. Therefore, close follow-up of these patients with UD is required to avoid upper tract damage and chronic renal failure. Bladder neck reconstruction is used mostly in exstrophy patients with acceptable results. However, in children with a neurogenic bladder the results are less favourable [759]. In most patients, the creation of a continent catheterisable stoma is necessary due to difficulties in performing the CIC via the urethra. In one series, 10% to a third still performed CIC via the urethra with a re-operation rates between 67% and 79% after a median follow-up between seven and ten years [760]. In patients who are still incontinent after a bladder outlet procedure, bladder neck closure with a continent catheterisable stoma is an option. The combination of a sling procedure together with a urethral lengthening procedure may improve the continence rates [761]. Bulking agents have a low success rate (10-40%), which is in most cases only temporary [762-764]. However, it does not adversely affect the outcome of further definite surgical procedures [762]. Bladder neck closure is often seen as the last resort to gain urinary continence in those patients with persistent urinary incontinence through the urethra. In girls, the transection is done between bladder neck and urethra and in boys above the prostate with preservation of the neurovascular bundle. It is an effective method to achieve continence together with a catheterisable cutaneous channel +/- augmentation as a primary or secondary procedure [765, 766]. A complication rate of up to a third and a vesicourethral/vesicovaginal fistula in up to 15% should be considered [767], together with a higher risk for bladder stones, bladder perforation and deterioration of the upper tract function, if the patient is not compliant with CIC and bladder irrigations [767, 768].

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3.12.4.8 Catheterisable cutaneous channel. In most patients with a neurogenic bladder IC is required. If this is not possible, or very time and/or resources consuming via the urethra, a continent cutaneous catheterisable channel should be offered as well as in those with bladder outlet procedures. It is especially beneficial to wheelchair-bound patients who often have difficulty with urethral catheterisation or are dependent on others to catheterise the bladder. In long-term studies the revision rate due to stenosis or incontinence can be as high as 50-60% depending on the type of channel [769, 770]. The stoma can be placed at the umbilicus or in the lower right abdominal wall using a VQZ plasty [771]. It should be carefully evaluated pre-operatively: it is extremely important that the patient can reach the stoma easily. Sometimes it has to be placed in the upper abdominal wall due to sever scoliosis mostly associated with obesity. 3.12.4.9 Continent and incontinent cutaneous urinary diversion Incontinent urinary diversion should be considered in patients who are not willing or able to perform a CIC and who need urinary diversion because of upper tract deterioration or gain urinary continence due to social reasons. In children and adolescents, the colonic conduit has shown to have less complications compared to the ileal conduit [772-775]. Total bladder replacement is extremely rare in children and adolescents, but may be necessary in some adults due to secondary malignancies or complications with urinary diversions. Any type of major bladder and bladder outlet construction should be performed in centres with sufficient experience in the surgical technique, and with experienced healthcare personnel to carry out post-operative follow-up [713, 776, 777]. Algorithms can be used for management of these patients (Figures 7 and 8). 3.12.5 Follow-up Neurogenic bladder patients require lifelong follow-up including not only urological aspects but also neurological and orthopaedic aspects. Regular investigation of upper and lower urinary tract is mandatory. In patients with changes of the function of the upper and/or lower urinary tract, a complete neurological re-investigation should be recommended including a total spine MRI to exclude a secondary tethered cord or worsening of the hydrocephalus. In addition, if some neurological changes are observed a complete investigation of the urinary tract should be undertaken. In those patients with urinary tract reconstruction using bowel segments, regulatory investigations concerning renal function, acid base balance and vitamin B12 status are mandatory to avoid metabolic complications. There is an increased risk for secondary malignancies in patients with a neurogenic bladder either with or without enteric bladder augmentations [723, 778-785]. Therefore, patients need to be informed of this risk and possible signs like haematuria. Although there are poor data on follow-up schemes to discover secondary malignancies, after a reasonable follow-up time (e.g. ten to fifteen years), an annual cystoscopy can be considered. 3.12.6 Self-organisation of patients As patients’ self-organisations can support the parents, caregivers and the patients in all aspects of their daily life, patients should be encouraged to join these organisations.

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Figure 7a: M  anagement of children with myelodysplasia with a neurogenic bladder Flowchart - First year of life First 12 months

Birthdischarge from the hospital

6-12 weeks

6 months

9 months

1 year

• Bladder-catheter until closure of the back has healed • Then start CIC + AB after peri-operative antibiotic is finished

• Medical history • Clinical examination • Blood pressure • Urine analysis, • Check + optimise bowel manageent

• Medical history, • Clinical examination • Urine analysis • Check and optimise bowel manageent

• Medical history • Clinical examination • Urine analysis • Check and optimise bowel management

• Medical history • Clinical examination • Blood pressure • Urine analysis • Check and optimise bowel management

At one week: • RBU • Creatinine

• RBU • Creatinine

• RBU • Creatinine

• RBU

• RBU • Creatinine

• Start CIC + teach the parents CIC. • After getting comfortable with the CIC, stop AB. • Check bowel management

• VUD or • VCUG & CMG, if VUD is not available

• CMG if first CMG showed a hostile or non-conclusive CMG

• Start oxybutynin if any sign of bladder overactivity

• Start AB if reflux and hostile bladder or non-conclusive VUD/CMG

• If Reflux present or febrile UTI, VUD or VCUG & CMG if no reflux or febrile UTI, CMG is ok

• Baseline DMSA • If no reflux or no UTI and low grade reflux, stop AB if given due to reflux and monitor urine with dip sticks at home

RBUS = Renal bladder ultrasound; UTI = urinary tract infection; VUD = videourodynamic; VCUG = voiding cystourethrography; CMG = cystometrogram; DMSA = dimercaptosuccinic acid; AB = antibiotics.

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Figure 7b: M  anagement of children with myelodysplasia with a neurogenic bladder Flowchart - 18 months - 4 years of age 18 months - 4 years

18 months

2 years

2.5 years

3 years

4 years

• Medical history • Clinical examination • Blood pressure • Urine analysis • Check and optimise bowel management • Check anticholinergic medication + adapt to weight

• Medical history • Clinical examination • Blood pressure • Urine analysis • Check and optimise bowel management • Check anticholinergic medication + adapt to weight

• Medical history • Clinical examination • Blood pressure • Urine analysis • Check and optimise bowel management • Check anticholinergic medication + adapt to weight

• Medical history • Clinical examination • Blood pressure • Urine analysis • Check and optimise bowel management • Check anticholinergic medication + adapt to weight

• Medical history • Clinical examination • Blood pressure • Urine analysis • Check and optimise bowel management • Check anticholinergic medication + adapt to weight

• RBUS

• RBUS • Creatinine

• RBUS

• RBUS • Creatinine

• RBUS • Creatinine

• CMG only, if there is still a hostile bladder or clinical status has changed

• If reflux present or febrile UTI, VUD or VCUG & CMG if no reflux or febrile UTI, CMG is ok

• CMG only, if clinical status has changed

• If Reflux present or febrile UTI, VUD or VCUG & CMG if no reflux or febrile UTI, CMG is ok

• If Reflux present or febrile UTI, VUD or VCUG & CMG if no hostile bladder and clinical no change CMG at 5 yrs. is ok

• If no reflux or no UTI + low-grade reflux, stop AB • If AB is given due to reflux + monitor urine with dip sticks at home

• If no reflux or no UTI + low grade reflux, stop AB • If AB is given due to reflux + monitor urine with dip sticks at home

• If no reflux or no UTI + low grade reflux, stop AB • If AB is given due to reflux + monitor urine with dip sticks at home

RBUS = Renal bladder ultrasound; UTI = urinary tract infection; VUD = videourodynamic; VCUG = voiding cystourethrography; CMG = cystometrogram; DMSA = dimercaptosuccinic acid; AB = antibiotics

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Figure 7c: M  anagement of children with myelodysplasia with a neurogenic bladder Flowchart - 5 years to adulthood

5 years - adulthood

5 years

6 years - puberty yearly

Adolescence yearly

Adulthood yearly

• Medical history • Clinical examination • Blood pressure • Urine analysis • Check and optimise bowel management • Check anticholinergic medication + adapt to weight

• Medical history • Clinical examination • Blood pressure • Urine analysis • Check and optimise bowel management • Check anticholinergic medication + adapt to weight

• Medical history • Clinical examination • Blood pressure • Urine analysis • Check and optimise bowel management • Discuss sexual function/fertility • Check anticholinergic medication + adapt to weight

• Medical history • Clinical examination • Blood pressure • Urine analysis • Check and optimise bowel management • Discuss sexual function + treat accordingly • Check anticholinergic medication + adapt to weight

• RBUS • Creatinine • Cystatin C

• RBUS • Creatinine • Cystatin C

• RBUS • Creatinine • Cystatin C

• RBUS • Creatinine • Cystatin C

• If Reflux present or febrile UTI, VUD or VCUG & CMG • If no reflux or febrile UTI, CMG is ok

• If no hostile bladder or clinical changes biannually CMG

• If no hostile bladder or clinical changes in a compliant patient biannually CMG otherwise yearly

• If no hostile bladder or clinical changes in a compliant patient biannually CMG otherwise yearly

• DMSA scan, if reflux was/is present or febrile UTI has occurred

• DMSA scan at age of 10, if reflux was/is present or febrile UTI has occurred

• DMSA scan at age of 15, if reflux was/is present or febrile UTI has occurred

• DMSA scan if indicated

• In patients with bowel segments incorporated into the urinary tract • Acid-base balance • Vitamin B12 • If pathological substitution

• In patients with bowel segments incorporated into the urinary tract • Acid-base balance • Vitamin B12 • If pathological substitution

• In patients with bowel segments incorporated into the urinary tract • Acid-base balance • Vitamin B12 • If pathological substitution • Check for secondary malignancy

RBUS = Renal bladder ultrasound; UTI = urinary tract infection; VUD = videourodynamic; VCUG = voiding cystourethrography; CMG = cystometrogram; DMSA = dimercaptosuccinic acid.

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Figure 8: Algorithm for the management of children with myelodysplasia with a neurogenic bladder

Time at diagnosis

Late presentation

Newborn

Early CIC

Understanding the detrussor-sphincter relationship status: history, USG, VUD/VCU, nuclear medicine

Detrussor overactive, Sphincter under/normoactive

Detrussor overactive, Sphincter overactive

Detrussor underactive, Sphincter over/normoactive

Detrussor underactive, Sphincter underactive

Antimuscarinic CIC if residual urine CAP if VUR present

Antimuscarinic CIC CAP if VUR present

CIC if residual urine CAP if VUR present

CIC if residual urine CAP if VUR present

In cases of clinical failure or upper urinary tract deterioration: Botulinum toxin injection to bladder: added to treatment

In cases of clinical failure or upper urinary tract deterioration: Botulinum toxin injection to bladder or sphincter: added to treatment

Decision given regarding the clinical situation

Bladder neck procedures +/- augmentation procedures

Augmentation procedures

Augmentation procedures

In failed cases bladder neck closure Or urinary diversion

CAP = continuous antibiotic prophylaxis; CIC = clean intermittent catheterisation; US = ultrasound; VCUG = voiding cystourethrography; VUD = videourodynamic; VUR = vesicoureteric reflux.

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3.12.7

Summary of evidence and recommendations for the management of neurogenic bladder

Summary of evidence Neurogenic detrusor-sphincter dysfunction (NDSD) may result in different forms of LUTD and ultimately result in incontinence, UTIs, VUR, and renal scarring. In children, the most common cause of NDSD is myelodysplasia (a group of developmental anomalies that result from defects in neural tube closure). Bladder sphincter dysfunction correlates poorly with the type and level of the spinal cord lesion. Therefore, urodynamic and functional classifications are more practical in defining the extent of the pathology and in guiding treatment planning. Children with neurogenic bladder can have disturbances of bowel function as well as urinary function which require monitoring and, if needed, management. The main goals of treatment are prevention of urinary tract deterioration and achievement of continence at an appropriate age. Injection of botulinum toxin into the detrusor muscle in children who are refractory to anticholinergics, has been shown to have beneficial effects on clinical and urodynamic variables. Recommendations Urodynamic studies should be performed in every patient with spina bifida as well as in every child with high suspicion of a neurogenic bladder to estimate the risk for the upper urinary tract and to evaluate the function of the detrusor and the sphincter. In all newborns, intermittent catheterisation (IC) should be started soon after birth. In those with a clear underactive sphincter and no overactivity starting IC may be delayed. If IC is delayed, closely monitor babies for urinary tract infections, upper tract changes (US) and the lower tract (UD). Start early anticholinergic medication in the newborns with suspicion of an overactive detrusor. The use of suburothelial or intradetrusoral injection of onabotulinum toxin A is an alternative and a less invasive option in children who are refractory to anticholinergics in contrast to bladder augmentation. Treatment of faecal incontinence is important to gain continence and independence. Treatment should be started with mild laxatives, rectal suppositories as well as digital stimulation. If not sufficient transanal irrigation is recommended, if not practicable or feasible, a Malone antegrade colonic enema (MACE)/Antegrade continence enema (ACE) stoma should be discussed. Ileal or colonic bladder augmentation is recommended in patients with therapy resistant overactivity of the detrusor, small capacity and poor compliance, which may cause upper tract damage and incontinence. The risk of surgical and nonsurgical complications and consequences outweigh the risk of permanent damage of the upper urinary tract +/- incontinence due to the detrusor. In patients with a neurogenic bladder and a weak sphincter, a bladder outlet procedure should be offered. It should be done in most patients together with a bladder augmentation. Creation of a continent cutaneous catheterisable channel should be offered to patients who have difficulties in performing an IC through the urethra. A life-long follow-up of renal and reservoir function should be available and offered to every patient. Addressing sexuality and fertility starting before/during puberty should be offered. Urinary tract infections are common in children with neurogenic bladders, however, only symptomatic UTIs should be treated.

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3.13

Dilatation of the upper urinary tract (UPJ and UVJ obstruction)

3.13.1 Epidemiology, aetiology and pathophysiology Dilatation of the upper urinary tract (UUT) remains a significant clinical challenge in deciding which patient will benefit from treatment. Ureteropelvic junction (UPJ) obstruction is defined as impaired urine flow from the pelvis into the proximal ureter with subsequent dilatation of the collecting system and the potential to damage the kidney. It is the most common pathological cause of neonatal hydronephrosis [786]. It has an overall incidence of 1:1,500 and a ratio of males to females of 2:1 in newborns. Ureterovesical junction (UVJ) obstruction is an obstructive condition of the distal ureter as it enters the bladder, commonly called a primary obstructive megaureter. Megaureters are the second most likely cause of pathological neonatal hydronephrosis. They occur more often in males and are more likely to occur on the left side [787]. It can be very difficult to define ‘obstruction’ as there is no clear division between ‘obstructed’ and ‘non-obstructed’ urinary tracts. Currently, the most popular definition is that an obstruction represents any restriction to urinary outflow that, if left untreated, will cause progressive renal deterioration [788]. 3.13.2 Diagnostic evaluation The widespread use of US during pregnancy has resulted in a higher detection rate for antenatal hydronephrosis [789]. The challenge in the management of dilated UUT is to decide which child should be observed, which should be managed medically, and which requires surgical intervention. Despite the wide range of diagnostic tests, there is no single test that can accurately distinguish obstructive from nonobstructive cases (see Figure 9). 3.13.2.1 Antenatal ultrasound Usually between the 16th and 18th weeks of pregnancy, the kidneys are visualised routinely, when almost all amniotic fluid consists of urine. The most sensitive time for foetal urinary tract evaluation is the 28th week. If dilatation is detected, US should focus on: • laterality, severity of dilatation, and echogenicity of the kidneys; • hydronephrosis or hydro-ureteronephrosis; • bladder volume and bladder emptying; • sex of the child; • amniotic fluid volume [790]. 3.13.2.2 Postnatal ultrasound Since transitory neonatal dehydration lasts about 48 hours after birth, imaging should be performed following this period of postnatal oliguria. However, in severe cases (bilateral dilatation, solitary kidney, oligohydramnios), immediate postnatal sonography is recommended [791]. Ultrasound should assess the anteroposterior diameter of the renal pelvis, calyceal dilatation, kidney size, thickness of the parenchyma, cortical echogenicity, ureters, bladder wall and residual urine. 3.13.2.3 Voiding cystourethrogram In newborns with identified UUT dilatation, the primary or important associated factors that must be detected include: • vesicoureteral reflux (found in up to 25% of affected children) [792]; • urethral valves; • ureteroceles; • diverticula; • neurogenic bladder. Conventional VCUG is the method of choice for primary diagnostic procedures [793]. 3.13.2.4 Diuretic renography Diuretic renography is the most commonly used diagnostic tool to detect the severity and functional significance of problems with urine transport. Technetium-99m (99mTc) mercaptoacetyltriglycine (MAG3) is the radionuclide of choice. It is important to perform the study under standardised circumstances (hydration, transurethral catheter) after the fourth and sixth weeks of life [794]. Oral fluid intake is encouraged prior to the examination. At fifteen minutes before the injection of the radionuclide, it is mandatory to administer normal saline intravenous infusion at a rate of 15 mL/kg over 30 minutes, with a subsequent maintenance rate of 4 mL/ kg/h throughout the entire time of the investigation [795]. The recommended dose of furosemide is 1 mg/kg for infants during the first year of life, while 0.5 mg/kg should be given to children aged one to sixteen years, up to a maximum dose of 40 mg.

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Figure 9: Diagnostic algorithm for dilatation of the upper urinary tract Postnatal US

Dilatation (uni- or bilateral)

No dilatation

Voiding cystourethrogram (VCUG)*

Repeat US after 4 weeks

Diuretic renography

* A diagnostic work-up including VCUG must be discussed with the caregivers, as it is possible that, even if reflux is detected, it may have absolutely no clinical impact. However, it should be borne in mind that reflux has been detected in up to 25% of cases of prenatally detected and postnatally confirmed hydronephrosis [695]. US = ultrasound. 3.13.3 Management 3.13.3.1 Prenatal management Counselling the caregivers of an affected child is one of the most important aspects of care. The prognosis is hopeful for a hydronephrotic kidney, even if it is severely affected, as it may still be capable of meaningful renal function, unlike a severely hypoplastic and dysplastic kidney. It is important to be able to tell the caregivers exactly when they will have a definitive diagnosis for their child and what this diagnosis will mean. In some cases, however, it will be immediately obvious that the child is severely affected; there will be evidence of massive bilateral dilatation, bilateral hypoplastic dysplasia, progressive bilateral dilatation with oligohydramnios, and pulmonary hypoplasia. Intrauterine intervention is rarely indicated and should only be performed in well-experienced centres [796]. 3.13.3.1.1 Antibiotic prophylaxis for antenatal hydronephrosis The benefits and harms of continous antibiotic prophylaxis (CAP) vs. observation in patients with antenatal hydronephrosis are controversial. Currently, only two RCTs have been published, one of which is a pilot trial [797] and the other publication is only available as a congress abstract [798]. Both publications present incomplete data and outcomes. The Panel conducted a SR assessing the literature from 1980 onwards [799]. The key findings are summarised below. Due to the heterogeneity of the published literature it was not possible to draw strong conclusions as to whether CAP is superior to observation alone in children diagnosed with antibiotic prophylaxis for antenatal hydronephrosis (ANH). In the first RCT, a prospective longitudinal study [797], female gender, uncircumcised males, lack of CAP, high-grade hydronephrosis, hydroureteronephrosis and VUR were found to be the independent predictors for the development of UTI. The second RCT included in the SR, was published as an abstract only, presented limited data [798]. This trial seemed to focus mainly on patients with ANH and VUR and did not report any beneficial effect of CAP on UTI rates, but details on the study population were limited. Key findings of the SR are that CAP may or may not be superior to observation in children with antenatal hydronephrosis in terms of decreasing UTI. Due to the low data quality it was also not possible to establish whether boys or girls are at a greater risk of developing a UTI, or ascertain whether the presence or absence of VUR impacts UTI rates. A correlation between VUR-grade and UTI could not be established either. However, noncircumcised infants, children diagnosed with high-grade hydronephrosis and hydroureteronephrosis were shown to be at higher risk of developing a UTI. The SR also tried to identify the most effective antibiotic regimen and present data on adverse effects but, due to heterogeneity, the available data could not be statistically compared. The most commonly used antibiotic in infants with antenatal hydronephrosis is trimethoprim, but only one study reported side effects [797].

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In conclusion, based on the available evidence, the benefits and harms of CAP in children with antenatal hydronephrosis remain unproven. Uncircumcised infants and infants with hydroureteronephrosis and highgrade hydronephrosis are more likely to develop a UTI. Continuous antibiotic prophylaxis should be reserved for this sub-group of children who are proven to be at high risk. 3.13.3.2 UPJ obstruction It is most important that management decisions are made on the basis of serial investigations that have used the same technique and have been performed by the same institution under standardised circumstances. According to a Cochrane review, non-surgical management of unilateral UPJ obstruction in infants less than 2 years old is also an option. However the high risk of bias of the included studies limits the evidence of this systematic review [800]. Symptomatic obstruction (recurrent flank pain, UTI) requires surgical correction using a pyeloplasty, according to the standardised open technique of Hynes and Anderson [801]. In experienced hands, laparoscopic or retroperitoneoscopic techniques and robot-assisted techniques have the same success rates as standard open procedures. In asymptomatic cases, conservative follow-up is the treatment of choice. A recent interventional study suggested that, in operated infants less than six months, inserting a stent (transanastomotic stent) decreases the complication rates compared to stentless approach [802]. However the results should be taken cautiously since there are successful reported stentless procedures in other age groups. Indications for surgical intervention comprise impaired split renal function (< 40%), a decrease of split renal function of > 10% in subsequent studies, poor drainage function after the administration of furosemide, increased anteroposterior diameter on US, and grade III and IV dilatation as defined by the Society for Fetal Urology [593]. Well-established benefits of conventional laparoscopy over open surgery are the decreased length of hospital stay, better cosmesis, less post-operative pain and early recovery [803, 804]. A recent meta-analysis in children has shown that laparoscopic pyeloplasty (LP) was associated with decreased length of hospital stay and complication rates but prolonged operative time when compared to open pyeloplasty (OP). Additionally, both LP and OP had equal success rates [805]. Laparoscopic pyeloplasty can also be performed for re-do cases with the same advantages of the primary cases [806]. Robotic-assisted laparoscopic pyeloplasty (RALP) has all the same advantages as LP plus better manoeuvrability, improved vision, ease in suturing and increased ergonomics but higher costs [807, 808]. A recent study comparing RALP and LP has shown similar postoperative outcomes with exception of decreased operative time for RALP [809]. There does not seem to be any clear benefit of minimal invasive procedures in a very young child but current data is insufficient to defer a cut-off age. 3.13.3.3 Megaureter The treatment options of secondary megaureters are reviewed in Chapter 3.14.3. 3.13.3.3.1 Non-operative management If a functional study reveals and confirms adequate ureteral drainage, conservative management is the best option. Initially, low-dose prophylactic antibiotics within the first year of life are recommended for the prevention of UTIs, although there are no existing prospective randomised trials evaluating the benefit of this regimen [810]. With spontaneous remission rates of up to 85% in primary megaureter cases, surgical management is no longer recommended, except for megaureters with recurrent UTIs, deterioration of split renal function and significant obstruction [811]. 3.13.3.3.2 Surgical management In general, surgery is indicated for symptomatic children, if there is a drop in function in conservative follow-up and hydroureteronephrosis is increasing [812]. Data suggest that children with a ureteric diameter of > 10-15 mm are more likely to require intervention [813]. The initial approach to the ureter can be either intravesical, extravesical or combined. Straightening the ureter is necessary without devascularisation. Ureteral tapering should enhance urinary flow into the bladder. The ureter must be tapered to achieve a diameter for an anti-reflux repair. Several tailoring techniques exist, such as ureteral imbrication or excisional tapering [814]. Some institutions perform endoscopic stenting, but there are still no long-term data and no prospective randomised trials to confirm their outcome. A systematic review assessed the success rates of endoscopic management of primary obstructive megaureters [815]. It was reported that endoscopic managements including; stent placement, balloon dilatation and incision can be an alternative treatment in patients > 1 years of age. One third of those patients required further surgical correction. Furthermore, the long-term outcome of endoscopic management is still unknown. Therefore the EAU Paediatric Urology Guidelines Panel can not recommend endoscopic management routinely since the type of intervention and the management outcomes are unclear.

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3.13.4 Conclusion The use of routine perinatal sonography has resulted in increased detection of hydronephrosis caused by UPJ or UVJ obstruction. Meticulous and repeat postnatal evaluation is mandatory to try to identify obstructive cases at risk of renal deterioration and requiring surgical reconstruction. Surgical methods are standardised and have a good clinical outcome. 3.13.5

Summary of evidence and recommendations for the management of UPJ-, UVJ-obstruction

Summary of evidence Nowadays, most hydronephrotic kidneys have already been diagnosed prenatally during a maternal US investigation. Ureteropelvic junction obstruction is the leading pathological cause of hydronephrotic kidneys (40%). In children diagnosed with antenatal hydronephrosis, a systematic review could not establish any benefits or harms related to continuous antibiotic prophylaxis. In children diagnosed with antenatal hydronephrosis, non-circumcised infants (LE: 1a), children diagnosed with high-grade hydronephrosis (LE: 2) and hydroureteronephrosis (LE: 1b) were shown to be at higher risk of developing UTI. Recommendations Include serial ultrasound (US) and subsequent diuretic renogram and sometimes voiding cystourethrography in post-natal investigations. Offer continuous antibiotic prophylaxis to the subgroup of children with antenatal hydronephrosis who are at high risk of developing urinary tract infection like uncircumcised infants, children diagnosed with hydroureteronephrosis and highgrade hydronephrosis, respectively. Decide on surgical intervention based on the time course of the hydronephrosis and the impairment of renal function. Offer surgical intervention in case of an impaired split renal function due to obstruction or a decrease of split renal function in subsequent studies and increased anteroposterior diameter on the US, and grade IV dilatation as defined by the Society for Fetal Urology. Offer pyeloplasty when ureteropelvic junction obstruction has been confirmed clinically or with serial imaging studies proving a substantially impaired or decrease in function. Do not offer surgery as a standard for primary megaureters since the spontaneous remission rates are as high as 85%.

3.14

LE 2 1 1b 2

LE 2

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Strong

Vesicoureteric reflux

Lack of robust prospective RCTs limits the strength of the established guidelines for the management of VUR. The scientific literature for reflux disease is still limited and the level of evidence is generally low. Most of the studies are retrospective, include different patient groups, and have poor stratification of quality. Also, there is a high risk of presenting misleading results by combining different types of studies when systematically extracting data. Therefore, for reflux disease, it is unfortunately not possible to produce recommendations based on high-quality studies. The Panel have assessed the current literature, but in the absence of conclusive findings, have provided recommendations based on Panel consensus. These Guidelines aim to provide a practical approach to the treatment of VUR based on risk analysis and selective indications for both diagnostics and intervention. Although the Panel have tried to summarise most of the possible scenarios in one single table, the table itself is still quite busy. The Panel strongly share the view that making simple and practical guidelines would underestimate the complexity of VUR as a sign of a wide range of pathologies [816]. 3.14.1 Epidemiology, aetiology and pathophysiology Vesicoureteric reflux is an anatomical and/or functional disorder with potentially serious consequences, such as renal scarring, hypertension and renal failure. Patients with VUR present with a wide range of severity, and a good proportion of reflux patients do not develop renal scars and probably do not need any intervention [817]. Vesicoureteric reflux is a very common urological anomaly in children, with an incidence of nearly 1%.

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The main management goal is the preservation of kidney function, by minimising the risk of pyelonephritis. By defining and analysing the risk factors for each patient (i.e. age, sex, reflux grade, LUTD, anatomical abnormalities, and kidney status), it is possible to identify those patients with a potential risk of UTIs and renal scarring. Controversy persists over the optimal management of VUR, particularly the choice of diagnostic procedures, treatment (medical, endoscopic or surgical), and the timing of treatment. Many children present without symptoms of UTI and, because invasive diagnostic procedures are performed only when clinically indicated, the exact prevalence of VUR is unknown. However, the prevalence of VUR in non-symptomatic children has been estimated at 0.4-1.8% [818]. Among infants prenatally identified with hydronephrosis on US, who were screened for VUR, the prevalence was 16.2% (7-35%) [819]. Siblings of children with VUR had a 27.4% (3-51%) risk of also having VUR, whereas the offspring of parents with VUR had a higher incidence of 35.7% (21.2-61.4%) [819]. However, reflux detected by sibling screening is associated with lower grades [718] and significantly earlier resolution [820]. When VUR is discovered in siblings after UTI, it is usually high-grade and associated with a high incidence of reflux nephropathy, particularly if the sibling is male and the grade of reflux was high in the index patient [821]. The incidence of VUR is much higher among children with UTIs (30-50%, depending on age). Urinary tract infections are more common in girls than boys due to anatomical differences. However, among all children with UTIs, boys are more likely to have VUR than girls (29% vs. 14%). Boys also tend to have higher grades of VUR diagnosed at younger ages, although their VUR is more likely to resolve itself [822-825]. There is a clear co-prevalence between LUTD and VUR [826]. Lower urinary tract dysfunction refers to the presence of LUTS, including urge, urge incontinence, weak stream, hesitancy, frequency and UTIs, which reflect the filling and/or emptying dysfunction and may be accompanied with bowel problems [826]. Some studies have described a prevalence of 40-60% for VUR in children with LUTD [827]. A published Swedish reflux trial has demonstrated LUTD in 34% of patients, and subdivision into groups characteristic of children revealed that 9% had isolated overactive bladder and 24% had voiding phase dysfunction [828]. The spontaneous resolution of VUR is dependent on age at presentation, sex, grade, laterality, mode of clinical presentation, and anatomy [820]. Faster resolution of VUR is more likely with age less than one year at presentation, lower grade of reflux (grade 1-3), and asymptomatic presentation with prenatal hydronephrosis or sibling reflux. The overall resolution rate is high in congenital high-grade VUR during the first years of life. In several Scandinavian studies, the complete resolution rate for high-grade VUR has been reported at > 25%, which is higher than the resolution rate for VUR detected after infancy [828-830]. The presence of renal cortical abnormality, bladder dysfunction, and breakthrough febrile UTIs are negative predictive factors for reflux resolution [831-833]. Dilating VUR increases the risk of developing acute pyelonephritis and renal scarring. Untreated recurrent UTIs may have a negative impact on somatic growth and medical status of the child. Evidence of renal scarring is present in 10-40% of children with symptomatic VUR, resulting from either congenital dysplasia and/or acquired post-infectious damage, which may have a negative impact on somatic growth and general well-being [834-836]. Scar rates vary in different patient groups. Patients with higher grades of VUR present with higher rates of renal scars. In those with prenatal hydronephrosis, renal scarring occurs in 10% of patients [837-842], whereas in patients with LUTD, this may increase up to 30% [605, 836, 843]. Renal scarring may adversely affect renal growth and function, with bilateral scarring increasing the risk of insufficiency. Reflux nephropathy (RN) may be the most common cause of childhood hypertension. Follow-up studies have shown that 10-20% of children with RN develop hypertension or end-stage renal disease [844]. 3.14.2 Diagnostic evaluation The diagnostic work-up should aim to evaluate the overall health and development of the child, the presence of UTIs, renal status, the presence of VUR, and LUT function. A basic diagnostic work-up comprises a detailed medical history (including family history, and screening for LUTD), physical examination including blood pressure measurement, urinalysis (assessing proteinuria), urine culture, and serum creatinine in patients with bilateral renal parenchymal abnormalities. The standard imaging tests include renal and bladder US, VCUG and nuclear renal scans. The criterion standard in diagnosis of VUR is VCUG, especially at the initial work-up. This test provides precise anatomical detail and allows grading of VUR [845]. In 1985, the International Reflux Study Committee introduced a uniform system for the classification of VUR [846, 847] (Table 2). The grading system combines two earlier classifications and is based upon the extent of retrograde filling and dilatation of the ureter, renal pelvis and calyces on VCUG [847]. Radionuclide studies for detection of reflux have lower radiation exposure than VCUG, but the anatomical details depicted are inferior [848]. Recent studies on alternative imaging modalities for detection on VUR have yielded good results with voiding US and magnetic resonance VCUG [849-851]. Contrast

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enhanced voiding urosonography with intravesical instillation of different ultrasound contrast agents has been shown to be highly sensitive giving comparable results with conventional VCUG while avoiding exposure to ionising radiation [459, 852]. However, despite the concerns about ionising radiation and its invasive nature, conventional VCUG still remains the gold standard because it allows better determination of the grade of VUR (in a single or duplicated kidney) and assessment of the bladder and urethral configuration. Table 2: Grading system for VUR on VCUG, according to the International Reflux Study Committee [853] Grade I Grade II Grade III Grade IV Grade V

Reflux does not reach the renal pelvis; varying degrees of ureteral dilatation Reflux reaches the renal pelvis; no dilatation of the collecting system; normal fornices Mild or moderate dilatation of the ureter, with or without kinking; moderate dilatation of the collecting system; normal or minimally deformed fornices Moderate dilatation of the ureter with or without kinking; moderate dilatation of the collecting system; blunt fornices, but impressions of the papillae still visible Gross dilatation and kinking of the ureter, marked dilatation of the collecting system; papillary impressions no longer visible; intraparenchymal reflux

Dimercaptosuccinic acid is the best nuclear agent for visualising the cortical tissue and differential function between both kidneys. Dimercaptosuccinic acid is taken up by proximal renal tubular cells and is a good indicator of renal parenchyma function. In areas of acute inflammation or scarring, DMSA uptake is poor and appears as cold spots. Dimercaptosuccinic acid scans are therefore used to detect and monitor renal scarring. A baseline DMSA scan at the time of diagnosis can be used for comparison with successive scans later during follow-up [854]. Dimercaptosuccinic acid can also be used as a diagnostic tool during suspected episodes of acute pyelonephritis [855]. Children with a normal DMSA scan during acute UTI have a low-risk of renal damage [855, 856]. Video-urodynamic studies are only important in patients in whom secondary reflux is suspected, such as those with spina bifida or boys in whom VCUG is suggestive of PUV. In the case of LUTS, diagnosis and follow-up can be limited to non-invasive tests (e.g. voiding charts, US, or uroflowmetry) [826]. Cystoscopy has a limited role in evaluating reflux, except for infravesical obstruction or ureteral anomalies that might influence therapy. 3.14.2.1 Infants presenting with prenatally diagnosed hydronephrosis Ultrasound of the kidney and bladder is the first standard evaluation tool for children with prenatally diagnosed hydronephrosis. It is non-invasive and provides reliable information regarding kidney structure, size, parenchymal thickness and collecting system dilatation [857, 858]. Ultrasound should be delayed until the first week after birth because of early oliguria in the neonate. It is essential to evaluate the bladder, as well as the kidneys. The degree of dilatation in the collecting system under US, when the bladder is both full and empty, may provide significant information about the presence of VUR. Bladder wall thickness and configuration may be an indirect sign of LUTD and reflux. The absence of hydronephrosis on postnatal US excludes the presence of significant obstruction; however, it does not exclude VUR. Monitoring with careful US avoids unnecessary invasive and irradiating examinations. The first two US scans within the first one to two months of life are highly accurate for defining the presence or absence of renal pathology. In infants with two normal, successive scans, VUR is rare, and if present it is likely to be low-grade [837, 859]. The degree of hydronephrosis is not a reliable indicator for the presence of VUR, even though cortical abnormalities are more common in high-grade hydronephrosis [819]. The presence of cortical abnormalities on US (defined as cortical thinning and irregularity, as well as increased echogenicity) warrants the use of VCUG for detecting VUR [819]. Dimercaptosuccinic acid provides more reliable and quantitative measurement of the degree of cortical abnormalities, first detected with US. The use of VCUG is recommended in patients with US findings of bilateral high-grade hydronephrosis, duplex kidneys with hydronephrosis, ureterocele, ureteric dilatation, and abnormal bladders, because the likelihood of VUR is much higher. In all other conditions, the use of VCUG to detect reflux is optional [819, 839, 860-862]. When infants who are diagnosed with prenatal hydronephrosis become symptomatic with UTIs, further evaluation with VCUG should be considered [861]. Patients with severe hydronephrosis and those whose hydronephrosis is sustained or progressive, need further evaluation to exclude obstruction.

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3.14.2.2 Siblings and offspring of reflux patients The screening of asymptomatic siblings and offspring is controversial. Some authors think that early identification of children with VUR may prevent episodes of UTI and therefore renal scarring, whereas others think that screening asymptomatic individuals is likely to result in significant over-treatment of clinically insignificant VUR. In screened populations the prevalence of VUR is 27.4% in siblings and 35.7% in offspring [853]. The overall estimate for renal cortical abnormalities is 19.3% (11-54%), with 27.8% having renal damage in cohorts of symptomatic and asymptomatic children combined. In asymptomatic siblings only, the rate of renal damage is 14.4% (0-100%). Although early screening and therefore early diagnosis and treatment appears to be more effective than late screening in preventing further renal damage [819, 821, 863, 864], screening in all siblings and offspring cannot be recommended based on the available evidence. The lack of RCTs for screened patients to assess clinical health outcomes makes evidence-based guideline recommendations difficult. 3.14.2.3

Recommendations for paediatric screening of VUR

Recommendations Inform parents of children with vesicoureteric reflux (VUR) that siblings and offspring have a high prevalence of VUR. Use renal ultrasound (US) for screening of sibling(s). Use voiding cystourethrography if there is evidence of renal scarring on US or a history of urinary tract infection. Do not screen older toilet-trained children since there is no added value in screening for VUR.

Strength rating Strong Strong Weak Weak

3.14.2.4 Children with febrile urinary tract infections A routine recommendation of VCUG at zero to two years of age after the first proven febrile UTI is the safest approach as the evidence for the criteria to selecting patients for reflux detection is weak. Children with febrile infections and abnormal renal US findings may have higher risk of developing renal scars and they should all be evaluated for reflux [462]. If reflux is diagnosed, further evaluation has traditionally consisted of a DMSA scan. An alternative “top-down” approach is also an option, as suggested by several studies in the literature. This approach carries out an initial DMSA scan close to the time of a febrile UTI, to determine the presence of pyelonephritis, which is then followed by VCUG if the DMSA scan reveals kidney involvement. A normal DMSA scan with no subsequent VCUG will fail to identify VUR in 5-27% of cases, with the missed VUR presumably being less significant. In contrast, a normal DMSA scan with no VCUG avoids unnecessary VCUG in > 50% of those screened [452, 865-867]. 3.14.2.5 Children with lower urinary tract symptoms and vesicoureteric reflux Detection of LUTD is essential in treating children with VUR. It is suggested that reflux with LUTD resolves faster after LUTD correction, and that patients with LUTD are at higher risk for developing UTI and renal scarring [825, 868]. The co-existence of both conditions should be explored in any patient who has VUR. If there are symptoms suggestive of LUTD (e.g. urgency, wetting, constipation or holding manoeuvres), an extensive history and examination, including voiding charts, uroflowmetry and residual urine determination, will reliably diagnose underlying LUTD. Among toilet-trained children, those with both LUTD and VUR are at higher risk of developing recurrent UTIs than children with isolated VUR [490]. In LUTD, VUR is often low-grade and US findings are normal, and there is no indication for performing VCUG in all children with LUTD, but the presence of febrile infections should be meticulously investigated. The co-existence of LUTD and VUR means it would be better to do a test covering both conditions, such as a VUDS. Any patient with LUTD and a history of febrile UTI should be investigated with a VUDS, if available. Furthermore, any child who fails standard therapy for LUTD should undergo urodynamic investigation. At this stage, combining a urodynamic study with VCUG is highly recommended.

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3.14.3 Disease management There are two main treatment approaches: conservative (non-surgical and surgical). 3.14.3.1 Non-surgical therapy The objective of conservative therapy is prevention of febrile UTI. It is based on the understanding that: • Vesicoureteric reflux resolves spontaneously, mostly in young patients with low-grade reflux. Resolution is nearly 80% in VUR grades I and II and 30-50% in VUR grades III-V within four to five years of follow-up. • Spontaneous resolution is low for bilateral high-grade reflux [869]. • Vesicoureteric reflux does not damage the kidney when patients are free of infection and have normal LUT function. • There is no evidence that small scars can cause hypertension, renal insufficiency or problems during pregnancy. Indeed, these are possible only in cases of severe bilateral renal damage. • The conservative approach includes watchful waiting, intermittent or continuous antibiotic prophylaxis, and bladder rehabilitation in those with LUTD [605, 868, 870-872]. • Circumcision during early infancy may be considered as part of the conservative approach because it is effective in reducing the risk of infection in normal children [873]. 3.14.3.1.1 Follow-up Regular follow-up with imaging studies (e.g. VCUG, nuclear cystography, or DMSA scan) is part of the conservative management to monitor spontaneous resolution and kidney status. Conservative management should be dismissed in all cases of febrile breakthrough infections, despite prophylaxis, and intervention should be considered. 3.14.3.1.2 Continuous antibiotic prophylaxis Vesicoureteral reflux increases the risk of UTI and renal scarring especially when in combination with LUTD. Many prospective studies have evaluated the role of continuous antibiotic prophylaxis in the prevention of recurrent UTI and renal scarring. It is clear that antibiotic prophylaxis may not be needed in every reflux patient [874-876]. Trials show the benefit of CAP is none or minimal in low-grade reflux. Continuous antibiotic prophylaxis is useful in patients with grade III and IV reflux in preventing recurrent infections but its use in preventing further renal damage is not proven. Toilet-trained children and children with LUTD derive better benefit from CAP [876-881]. The RIVUR trial was the largest, randomised, placebo-controlled, double blind, multi-centre study, involving 607 children aged 2-72 months with grade I-IV VUR. The RIVUR study showed that prophylaxis reduced the risk of recurrent UTI by 50% but not renal scarring and its consequences (hypertension and renal failure), at the cost of increased antimicrobial resistance. The benefit of prophylaxis was insignificant in patients with grade III or IV VUR and in the absence of LUTD [882-885]. Additional review of the RIVUR data based on a risk classification system defines a high-risk group (uncircumcised males; presence of BBD and high grade reflux) who would benefit from a antibiotic prophylaxis significantly. Therefore selective prophylaxis for this group is recommended [886]. It may be difficult and risky to select patients who do not need CAP. A safe approach would be to use CAP in most cases. Decision-making may be influenced by the presence of risk factors for UTI, such as young age, high-grade VUR, status of toilet-training/LUTS, female sex, and circumcision status. Although the literature does not provide any reliable information about the duration of CAP in reflux patients, a practical approach would be to use CAP until after children have been toilet-trained and ensuring that there is no LUTD. Continuous antibiotic prophylaxis is mandatory in patients with LUTD and reflux. Active surveillance of UTI is needed after CAP is discontinued. The follow-up scheme and the decision to perform an anti-reflux procedure or discontinuation of CAP may also depend on personal preferences and the attitude of patients and caregivers. It is strongly advised that the advantages and disadvantages should be discussed in detail with the family. 3.14.3.2 Surgical treatment Surgical treatment can be carried out by endoscopic injection of bulking agents or ureteral re-implantation. 3.14.3.2.1 Subureteric injection of bulking materials With the availability of biodegradable substances, endoscopic subureteric injection of bulking agents has become an alternative to long-term antibiotic prophylaxis and open surgical intervention in the treatment of VUR in children. Using cystoscopy, a bulking material is injected beneath the intramural part of the ureter in a submucosal location. The injected bulking agent elevates the ureteral orifice and the distal ureter, so that coaptation is increased. This results in narrowing of the lumen, which prevents reflux of urine into the ureter, while still allowing its antegrade flow.

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Several bulking agents have been used over the past two decades, including polytetrafluoroethylene (PTFE or Teflon™), collagen, autologous fat, polydimethylsiloxane, silicone, chondrocytes, a solution of dextranomer/hyaluronic acid (Deflux™, Dexell®) and more recently polyacrylatepolyalcohol copolymer hydrogel (Vantris®) [887, 888]. Although the best results have been obtained with PTFE [889], due to concerns about particle migration, PTFE has not been approved for use in children [890]. Although they are all biocompatible, other compounds such as collagen and chondrocytes have failed to provide a good outcome. Deflux™ was approved by the USA FDA in 2001 for the treatment of VUR in children. Initial clinical trials have demonstrated that this method is effective in treating reflux [891]. Studies with long-term follow-up have shown that there is a high recurrence rate which may reach as high as 20% in two years [876]. In a meta-analysis [892] of 5,527 patients and 8,101 renal units, the reflux resolution rate (by ureter) following one treatment for grades I and II reflux was 78.5%, 72% for grade III, 63% for grade IV, and 51% for grade V. If the first injection was unsuccessful, the second treatment had a success rate of 68% and the third treatment 34%. The aggregate success rate with one or more injections was 85%. The success rate was significantly lower for duplicated (50%) vs. single (73%) systems, and neuropathic (62%) vs. normal (74%) bladders. Obstruction at UVJ may happen in the long term follow-up after endoscopic correction of reflux. Patients with high-grade reflux and dilated ureters are at risk of late obstruction. It is significantly more common when polyacrylate-polyalcohol copolymer is used as bulking substance [893-895]. Clinical validation of the effectiveness of anti-reflux endoscopy is currently hampered by the lack of methodologically appropriate studies. In the most recent prospective, randomised trials comparing three treatment arms: i) endoscopic injection; ii) antibiotic prophylaxis; iii) surveillance without antibiotic prophylaxis in 203 children aged one to two years with grade III/IV reflux, endoscopic treatment gave the highest resolution rate of 71% compared to 39% and 47% for treatment arms ii and iii, respectively, after two years’ follow-up. The recurrence rate at two years after endoscopic treatment was 20%. The occurrence of febrile UTIs and scar formation was highest in the surveillance group at 57% and 11%, respectively. New scar formation rate was higher with endoscopic injection (7%) compared with antibiotic prophylaxis (0%) [896]. Longer follow-up studies are needed to validate these findings. 3.14.3.2.2 Open surgical techniques Various intra- and extravesical techniques have been described for the surgical correction of reflux. Although different methods have specific advantages and complications, they all share the basic principle of lengthening the intramural part of the ureter by submucosal embedding of the ureter. All techniques have been shown to be safe with a low rate of complications and excellent success rates (92-98%) [897]. The most popular and reliable open procedure is cross trigonal re-implantation described by Cohen [895]. The main concern with this procedure is the difficulty of accessing the ureters endoscopically, if needed, when the child is older. Alternatives are suprahiatal re-implantation (Politano-Leadbetter technique) and infrahiatal re-implantation (Glenn-Anderson technique). If an extravesical procedure (Lich-Gregoir) is planned, cystoscopy should be performed pre-operatively to assess the bladder mucosa and the position and configuration of the ureteric orifices. In bilateral reflux, an intravesical anti-reflux procedure may be considered, because simultaneous bilateral extravesical reflux repair carries an increased risk of temporary post-operative urine retention [898]. Overall, all surgical procedures offer very high and similar success rates for correcting VUR. 3.14.3.2.3 Laparoscopy and robot-assisted There have been a considerable number of case series of transperitoneal, extravesical and pneumovesicoscopic intravesical ureteral re-implantation, which have shown the feasibility of the techniques. Various anti-reflux surgeries have been performed with the robot and the extravesical approach is the most commonly used. Although initial reports give comparable outcomes to their open surgical counterparts in terms of successful resolution of reflux, recent meta-analysis of results of Robotic-Assisted Laparoscopic Ureteral Reimplantation (RALUR) are within a wide range of variation and on average they are poor compared to open surgery. Operative times, costs and post-operative complications leading to secondary interventions are higher with RALUR but post-operative pain and hospital stay is less compared to open surgery [899-902]. Also, laparoscopic- or robotic-assisted approaches are more invasive than endoscopic correction and their advantages over open surgery are still debated. Therefore, at present, a laparoscopic approach cannot be recommended as a routine procedure. It can be offered as an alternative to the caregivers in centres where there is established experience [873, 903-911].

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3.14.4

Summary of evidence and recommendations for the management of vesicoureteric reflux in childhood

Summary of evidence There is no evidence that correction of persistent low-grade reflux (grades I-III) without symptoms and normal kidneys offers a significant benefit. The traditional approach of initial medical treatment after diagnosis and shifting to interventional treatment in case of breakthrough infections and new scar formation needs to be challenged, because the treatment should be tailored to different risk groups. Surgical correction should be considered in patients with persistent high-grade reflux (grades IV/V). There is no consensus about the timing and type of surgical correction. The outcome of open surgical correction is better than endoscopic correction for higher grades of reflux, whereas satisfactory results can be achieved by endoscopic injection for lower grades. The choice of management depends on the presence of renal scars, clinical course, grade of reflux, ipsilateral renal function, bilaterality, bladder function, associated anomalies of the urinary tract, age, compliance, and parental preference. Febrile UTI, high-grade reflux, bilaterality, and cortical abnormalities are considered to be risk factors for possible renal damage. The presence of LUTD is an additional risk factor for new scars. Recommendations Initially treat all patients diagnosed within the first year of life with continuous antibiotic prophylaxis, regardless of the grade of reflux or presence of renal scars. Offer immediate, parenteral antibiotic treatment for febrile breakthrough infections. Offer definitive surgical or endoscopic correction to patients with frequent breakthrough infections. Offer open surgical correction to patients with persistent high-grade reflux and endoscopic correction for lower grades of reflux. Initially manage all children presenting at age one to five years conservatively. Offer surgical repair to children above the age of one presenting with high-grade reflux and abnormal renal parenchyma. Offer close surveillance without antibiotic prophylaxis to children presenting with lower grades of reflux and without symptoms. Ensure that a detailed investigation for the presence of lower urinary tract dysfunction (LUTD) is done in all and especially in children after toilet-training. If LUTD is found, the initial treatment should always be for LUTD. Offer surgical correction, if parents prefer definitive therapy to conservative management. Select the most appropriate management option based on: • the presence of renal scars; • clinical course; • the grade of reflux; • ipsilateral renal function; • bilaterality; • bladder function; • associated anomalies of the urinary tract; • age and gender; • compliance; • parental preference. Refer to Table 3 for risk factors and follow-up. In high-risk patients who already have renal impairment, a more aggressive, multidisciplinary approach is needed.

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Strength rating Weak Strong Weak Strong Strong Weak Strong Strong

Strong Weak

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Table 3: Management and follow-up according to different risk groups Risk Groups High

High

Moderate

Moderate

Moderate

Presentation Symptomatic male or female patients after toilet-training with high-grade reflux (grades IV-V), abnormal kidneys and LUTD Symptomatic male or female patients after toilet-training with high-grade reflux (grade IV-V), abnormal kidneys and no LUTD Symptomatic male or female patients before toilet-training, with high-grade reflux and abnormal kidneys

Symptomatic male or female patients after toilet-training with low-grade reflux, abnormal kidneys with or without LUTD

Moderate

All symptomatic patients with normal kidneys, with lowgrade reflux, with LUTD All symptomatic patients with normal kidneys, with lowgrade reflux, with no LUTD All asymptomatic patients with normal kidneys with lowgrade reflux

Low

Follow-up More aggressive follow-up for UTI and LUTD; full re-evaluation after 6 months

Intervention should be Open surgery has considered better results than endoscopic surgery

Post-operative VCUG on indication only; follow-up of kidney status until after puberty

CAP is the initial treatment. Intervention may be considered in cases of BT infections or persistent reflux CAP is the Asymptomatic initial treatment. patients (PNH or Intervention may be sibling) with highconsidered in cases grade reflux and of BT, infections or abnormal kidneys persistent reflux Symptomatic male or Initial treatment is female patients after always for LUTD with CAP. Intervention toilet-training, with high-grade reflux and may be considered in cases of BT infections normal kidneys with or persistent reflux LUTD

Moderate

Low

Initial treatment Comment Greater possibility of Initial treatment is always for LUTD with earlier intervention CAP; intervention may be considered in cases of BT infections or persistent reflux

Choice of treatment is controversial. Endoscopic treatment may be an option. LUTD treatment should be given if needed Initial treatment is always for LUTD with or without CAP

Spontaneous resolution is higher in males

Follow-up for UTI/ hydronephrosis; full re-evaluation after 12-24 months

Follow-up for UTI/ hydronephrosis; full re-evaluation after 12-24 months

In case of persistent LUTD, despite urotherapy, intervention should be considered. The choice of intervention is controversial

Follow-up for UTI and LUTD, kidney status; full re-evaluation after successful urotherapy

Follow-up for UTI, LUTD, and kidney status until after puberty

Follow-up for UTI and LUTD

No treatment or CAP

Follow-up for UTI If no treatment is given, parents should be informed about risk of infection

No treatment or CAP in infants

Follow-up for UTI If no treatment is given, parents should be informed about risk of infection

BT = breakthrough; CAP = continuous antibiotic prophylaxis; LUTD = lower urinary tract dysfunction; PNH = prenatal diagnosed hydronephrosis; UTI = urinary tract infection; VCUG = voiding cystourethrography.

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3.15

Urinary stone disease

3.15.1 Epidemiology, aetiology and pathophysiology Paediatric stone disease is an important clinical problem in paediatric urology practice. Due to its recurrent nature, every effort should be made to discover the underlying metabolic abnormality so that it can be treated appropriately. Obtaining a stone-free state with close follow-up are of the utmost importance, although, it may not be possible in some circumstances (e.g. oxalosis or nephrocalcinosis). Bladder stones are still common in underdeveloped areas of the world and are usually ammonium acid urate and uric acid stones, strongly implicating dietary factors [912]. Patients with augmented bladder constitute another important group with a risk of up to 15% [913]. The incidence and characteristics of stones show a wide geographical variation in children. Although urinary stone disease is generally considered to be a relatively rare disease, it is quite common in some parts of the world. Paediatric stone disease is endemic in Turkey, Pakistan and in some South Asian, African and South American countries. However, recent epidemiological studies have shown that the incidence of paediatric stone disease is also increasing in the Western world [914-916], especially in girls, Caucasian ethnicity, African Americans and older children [917]. More than 70% of stones in children contain calcium oxalate, while infection stones are found more frequently in younger children [918]. 3.15.2 Classification systems Urinary stone formation is the result of a complex process involving metabolic, anatomical factors and presence of infection. 3.15.2.1 Calcium stones Calcium stones are usually made from calcium oxalate or calcium phosphate. Super-saturation of calcium (hypercalciuria) and oxalate (hyperoxaluria) or decreased concentration of inhibitors, such as citrate (hypocitraturia) or magnesium (hypomagnesemia) play a major role in the formation of calcium oxalate stones. Higher super-saturations of calcium oxalate was shown to be associated with multiple stone disease [919]. Hypercalciuria: This is defined by a 24-hour urinary calcium excretion of more than 4 mg/kg/day (0.1 mmol/kg/ day) in a child weighing < 60 kg. In infants younger than three months, 5 mg/kg/day (0.125 mmol/kg/day) is considered to be the upper limit for normal calcium excretion [920]. Hypercalciuria can be classified as either idiopathic or secondary. Idiopathic hypercalciuria is diagnosed when clinical, laboratory, and radiographic investigations fail to delineate an underlying cause leading to hypercalcaemia. Urinary calcium may increase in patients with high sodium chloride intake. Secondary hypercalciuria occurs when a known process produces excessive urinary calcium. In secondary hypercalcaemic hypercalciuria, a high serum calcium level may be due to increased bone resorption (hyperparathyroidism, hyperthyroidism, immobilisation, acidosis, metastatic disease) or gastrointestinal hyperabsorption (hypervitaminosis D) [921]. A good screening test for hypercalciuria compares the ratio of urinary calcium to creatinine. The normal calcium-to-creatinine ratio in children is less than 0.2. If the calculated ratio is higher than 0.2, repeat-testing is indicated. Neonates and infants have a higher calcium excretion and lower creatinine excretion than older children [920, 921]. If the follow-up ratios are normal, then no additional testing for hypercalciuria is needed. However, if the ratio remains elevated, a timed 24-hour urine collection should be obtained and the calcium excretion calculated. The 24-hour calcium excretion test is the standard criterion for the diagnosis of hypercalciuria. If calcium excretion is higher than 4 mg/kg/day (0.1 mmol/kg/day), the diagnosis of hypercalciuria is confirmed and further evaluation is warranted: levels of serum bicarbonate, creatinine, alkaline phosphatase, calcium, phosphorus, magnesium, pH, and parathyroid hormone. Freshly voided urine should be measured for pH [920922]. In addition to calcium, the 24-hour urine analysis should also include phosphorus, sodium, magnesium, uric acid, citrate and oxalate. Initial management is always to increase fluid intake and urinary flow. Dietary modification is a mandatory part of effective therapy. The child should be referred to a dietician to assess accurately the daily intake of calcium, animal protein, and sodium. Dietary sodium restriction is recommended as well as maintenance of calcium intake consistent with the daily needs of the child [923]. A brief trial of a low calcium diet can be carried out to determine if exogenous calcium intake and/or calcium hyperabsorption is contributing to high urinary calcium. Any recommendation to restrict calcium intake below the daily needs of the child should be avoided. Moreover, low calcium intake is a risk factor for stone formation [924] (LE: 3).

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Hydrochlorothiazide and other thiazide-type diuretics may be used to treat idiopathic hypercalciuria, especially with calcium renal leak, at a starting dosage of 0.5-1 mg/kg/day [925-928] (LE: 3). In long-term use of thiazide-type diuretics, a decrease in hypocalciuric effect may be seen after the third month and may cause hypokalemia, hypocitraturia, hyperuricaemia and hypomagnesaemia. Therefore, control of blood and serum values should be performed with regular intervals. Citrate therapy is also useful if citrate levels are low or if hypercalciuria persists, despite other therapies [925, 929] (LE: 4). Hyperoxaluria: Only 10-15% of oxalate comes from diet. The average child excretes less than 50 mg (0.57 mmol)/1.73 m2/day [930-932], while infants excrete four times as much. Hyperoxaluria may result from increased dietary intake, enteric hyperabsorption (as in short bowel syndrome) or an inborn error of metabolism. In rare primary hyperoxaluria, one of the two liver enzymes that play a role in the metabolism of oxalate may be deficient. With increased deposition of calcium oxalate in the kidneys, renal failure may ensue in resulting deposition of calcium oxalate in other tissues (oxalosis). The diagnosis is made upon laboratory findings of severe hyperoxaluria and clinical symptoms. The definitive diagnosis requires liver biopsy to assay the enzyme activity. Other forms of hyperoxaluria, as mentioned earlier, may be due to hyperabsorption of oxalate in inflammatory bowel syndrome, pancreatitis and short bowel syndrome. Yet, the majority of children have ‘mild’ (idiopathic) hyperoxaluria, with urine oxalate levels elevated only mildly in these cases. The treatment of hyperoxaluria consists of the promotion of high urine flow, restriction of dietary oxalate and regular calcium intake. Pyridoxine may be useful in reducing urine levels, especially in primary hyperoxaluria. Citrate administration increases inhibitory urine activity [925, 933] (LE: 4). Hypocitraturia: Citrate is a urinary stone inhibitor. Citrate acts by binding to calcium and by directly inhibiting the growth and aggregation of calcium oxalate as well as calcium phosphate crystals. Thus low urine citrate may be a significant cause of calcium stone disease. In adults, hypocitraturia is the excretion of citrate in urine of less than 320 mg/day (1.5 mmol/day) for adults; this value must be adjusted for children depending on body size [934-936]. Hypocitraturia usually occurs in the absence of any concurrent symptoms or any known metabolic derangements. It may also occur in association with any metabolic acidosis, distal tubular acidosis or diarrhoeal syndromes. Environmental factors that lower urinary citrate include a high protein intake and excessive salt intake. Many reports emphasise the significance of hypocitraturia in paediatric calcium stone disease. The presence of hypocitraturia ranges from 30% to 60% in children with calcium stone disease [935, 937]. The urine calcium-to-citrate ratios were higher in recurrent calcium stone forming children than solitary formers [934, 938]. The restoration of normal citrate levels is advocated to reduce stone formation, although there are few relevant studies in children. Hypocitraturia is treated by potassium citrate at a starting dose of 1 mEq/kg, given in two divided doses [926] (LE: 3). The side effects of potassium citrate are very rare and most of the time they include non-specific gastrointestinal complaints. Potassium citrate should be used with caution in hyperkalemic and chronic renal failure conditions. 3.15.2.2 Uric acid stones Uric acid stones are responsible for urinary calculi in 4-8% of children. Uric acid is the end product of purine metabolism. Hyperuricosuria is the main cause of uric acid stone formation in children. A daily output of uric acid of more than 10 mg/kg/day (0.6 mmol/kg/day) is considered to be hyperuricosuria [925]. The formation of uric acid stones is mainly dependent on the presence of acidic urinary composition. Uric acid dissociation and solubility is strongly reduced at pH of < 5.8. As the pH becomes more alkaline, uric acid crystals become more soluble and the risk of uric acid stone formation is reduced. In the familial or idiopathic form of hyperuricosuria, children usually have normal serum uric acid levels. In other children, it can be caused by uric acid overproduction secondary to inborn errors of metabolism, myeloproliferative disorders or other causes of cell breakdown. Hyperuricosuria is also caused by high purine and protein intake. Although hyperuricosuria is a risk factor for calcium oxalate stone formation in adults, this does not appear to be a significant risk factor in children. Uric acid stones are non-opaque stones. Plain X-rays are insufficient to show uric acid stones, and renal sonography and spiral CT are used for diagnosis.

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Alkalinisation of urine is the mainstay of therapy and prevention for uric acid stones. Citrate preparations are useful as alkalinising agents. Maintaining a urine pH of 6 to 6.5 is sufficient to prevent uric acid stones [925]. In patients who failed with conservative measures with sustaining hyperuricosuria and hyperuricemia, stone recurrences or myeloproliferative diseases, allopurinol (10 mg/kg) may be used. This medication may cause several drug reactions (rash, diarrhoea, eosinophilia) and should be cautiously used in chronic renal failure patients. 3.15.2.3 Cystine stones Cystinuria is the cause of cystine stone formation and accounts for 2-6% of all urinary stones in children. Cystinuria is an incompletely recessive autosomal disorder characterised by failure of renal tubules to reabsorb four basic amino acids: cystine, ornithine, lysine and arginine. Of these four amino acids, only cystine has poor solubility in urine, so that only cystine stones may form in the case of excessive excretion in urine. Cystine solubility is pH-dependent, with cysteine precipitation beginning at pH levels < 7.0. Other metabolic conditions, such as hypercalciuria, hypocitraturia and hyperuricosuria, may accompany cystinuria, so leading to the formation of mixed-composition stones. Cystine stones are faintly radiopaque and may be difficult to visualise on regular radiograph studies. They are also hard in texture and more difficult to disintegrate by extracorporeal shockwave lithotripsy (SWL). Cystinuric patients present with larger stones at the time of diagnosis, higher new stone formation rates, and are at higher risk of surgery [939]. The medical treatment for cystine stones aims to reduce cystine saturation in urine and increase its solubility. The initial treatment consists of maintaining a high urine flow and the use of alkalinising agents, such as potassium citrate to maintain urine pH at above 7.0 (better above 7.5). If this treatment fails, the use of α-mercaptopropionyl glycine or D-penicillamin may increase cystine solubility and reduce cystine levels in urine and prevent stone formation. Side effects of these drugs are mostly mild and include gastrointestinal complaints (alterations in taste and odour), fever and rash, however they can be associated with severe sideeffects, such as bone marrow depression, nephrotic syndrome and epidermolysis [940] (LE: 4). 3.15.2.4 Infection stones (struvite stones) Infection-related stones constitute nearly 5% of urinary stones in children, though incidence increases over 10% in younger ages [941] and in non-endemic regions [918, 942]. Bacteria capable of producing urease enzyme (Proteus, Klebsiella, Pseudomonas) are responsible for the formation of such stones. Urease converts urea into ammonia and bicarbonate, alkalinising the urine and further converting bicarbonate into carbonate. In the alkaline environment, triple phosphates form, eventually resulting in a supersaturated environment of magnesium ammonium phosphate and carbonate apatite, which in turn leads to stone formation. In addition to bacterial elimination, stone elimination is essential for treatment, as stones will harbour infection and antibiotic treatment will not be effective. Consideration should be given to investigating any congenital problem that causes stasis and infection. Genitourinary tract anomalies predispose to formation of such stones. 3.15.3 Diagnostic evaluation Presentation tends to be age-dependent, with symptoms such as flank pain and haematuria being more common in older children. Non-specific symptoms (e.g. irritability, vomiting) are common in very young children. Haematuria, usually visible, occurring with or without pain, is less common in children. However, nonvisible haematuria may be the sole indicator and is more common in children. In some cases, urinary infection may be the only finding leading to radiological imaging in which a stone is identified [943, 944]. 3.15.3.1 Imaging Generally, US should be used as a first approach. Renal US is very effective for identifying stones in the kidney. Many radiopaque stones can be identified with a simple abdominal flat-plate examination. The most sensitive test for identifying stones in the urinary system (especially for ureteric stones) is non-contrast helical CT scanning. It is safe and rapid, with 97% sensitivity and 96% specificity [945-947] (LE: 2). Despite its high diagnostic accuracy, because of the potential radiation hazards, its use should be reserved for cases with noninformative US and/or plain abdominal roentgenogram. Low dose protocols have also been developed with the goal of reducing radiation dose with adequate image quality [948]. Intravenous pyelography is rarely used in children, but may be needed to delineate the caliceal anatomy prior to percutaneous or open surgery.

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3.15.3.2 Metabolic evaluation Due to the high incidence of predisposing factors for urolithiasis in children and high stone recurrence rates, every child with a urinary stone should be given a complete metabolic evaluation [912, 940, 949, 950]. A limited urinary metabolic evaluation (24-h calcium, citrate, and oxalate and low urinary volume) is able to detect the vast majority of clinically significant metabolic abnormalities [951]. However collections are most of the time inadequate and should be repeated in this case [951, 952]. Metabolic evaluation includes: • family and patient history of metabolic problems and dietary habits; • analysis of stone composition (following stone analysis, metabolic evaluation can be modified according to the specific stone type); • electrolytes, blood/urea/nitrogen (BUN), creatinine, calcium, phosphorus, alkaline phosphatase, uric acid, total protein, carbonate, albumin, and parathyroid hormone (if there is hypercalcaemia); • spot urinalysis and culture, including ratio of calcium to creatinine; • urine tests, including a 24-hour urine collection for calcium, phosphorus, magnesium, oxalate, uric acid citrate, protein, and creatinine clearance; • 24-hour cystine analysis if cystinuria is suspected (positive sodium nitroprusside test, cystine stone, cystine hexagonal crystals in urine). Figure 10 provides an algorithm of how to perform metabolic investigations in urinary stone disease in children and how to plan medical treatment accordingly.

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Figure 10: Algorithm for metabolic investigations in urinary stone disease in children Paediatric stone patient Elimination of stones by spontaneous passage or active removal (SWL, surgery)

Exclude obstructive uropathy

Stone analysis

Mg Ammonium phosphate (struvite)

Uric acid stone

Cystine

urine culture

urine pH urine and serum uric acid levels

urine pH urine cystine level

possibly urease producing bacteria

acidicurine hyperuricosuria hyperuricemia

cystinuria

Total elimination of stone (surgery/SWL) antibiotics

serum PTH

Alkali replacementk- citrate Allopurinol (10 mg/kg) low purine diet

hypercalcaemia

Elevated

Calcium stones CaOX-CaPO

High fluid intake potassium citrate 3-4 mEq/kg/d mercaptopropiyonilglycine 10-15 mg/kg/d penicillamin 30 mg/kg/day

urine - blood pH urine - blood Ca - uric acid levels,urine Mg,pH Phosphate > 5.5 urine Ca-Oxalate-Citrate-Mg-Uric A -Phosphate

First morning urine pH < 5.5

Hyperparathyroidism Surgical treatment

First morning urine pH > 5.5 Further investigation for RTA

hypercalciuria

hyperoxaluria

hyperuricosuria

hypocitraturia

K-citrate diet (normal calcium low sodium intake) HCTZ (diuretic)

Regular calcium intake Diet low in ox. K-citrate pyridoxine

Alkali replacement (K-citrate) allopurinol

Citrate replacement K- citrate

Ca = calcium; HCTZ = hydrochlorothiazide; Mg = magnesium; Ox = oxalate; PTH = parathyroid hormone; SWL = extracorporeal shockwave lithotripsy; RTA = renal tubular acidosis; Uric A = uric acid. 3.15.4 Management Adequate fluid intake and restricting the use of salt within daily allowance range are the general recommendations besides the specific medical treatment against the detected metabolic abnormalities. With the advance of technology, stone management has changed from open surgical approaches to endoscopic techniques that are less invasive. Deciding on the type of treatment depends on the number, size, location, stone composition and the anatomy of the urinary tract [950, 953, 954]. Expectant management is the initial management in children with asymptomatic small size stones (< 4-5 mm ) with a possibility of spontaneous clearance. There is no consensus on the size of stones for different ages eligible for clearance and the duration of conservative follow-up. Adult literature reveals the benefits of medical expulsive therapy (MET) using α-blockers. Although, experience in children is limited showing different results [955], a meta-analysis of three randomised and two retrospective studies demonstrate that treatment with MET results in increased odds of spontaneous ureteral stone passage and a low rate of adverse events [956]. Currently, most paediatric

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stones can easily be managed by SWL. Endoscopic treatment can be applied for ureteric and bladder stones. Percutaneous removal of stones is also possible for kidney stones in children. Only a small portion of children will require open surgery but all attempts must be made to completely remove all stones since post-operative residual fragments pass spontaneously in only 20-25% of cases [957, 958]. A congenital obstructive uropathy should be managed together with stone removal therapy to prevent recurrence. 3.15.4.1 Extracorporeal shockwave lithotripsy Many reports confirm that SWL can be performed in children with no suspicion of long-term morbidity of the kidney [959-966]. The mean number of shockwaves for each treatment is approximately 1,800 and 2,000 (up to 4,000 if needed) and the mean power settings vary between 14 kV and 21 kV. The use of US and digital fluoroscopy has significantly decreased the radiation exposure and it has been shown that children are exposed to significantly lower doses of radiation compared to adults [953, 967, 968]. Concerns about anaesthesia no longer present a problem due to advances in technique and medication, even in the infant age group. The type of anaesthesia should be general or dissociative for children under ten years of age, whereas conventional intravenous sedation or patient-controlled analgesia is an option for older children who are able to co-operate [969] (LE: 2b). Stone-free rates are significantly affected by various factors. Regardless of the location, as the stone size increases, the stone-free rates decrease and retreatment rate increases. The stone-free rates for < 1 cm, 1-2 cm, > 2 cm and overall, were reported as nearly 90%, 80%, 60% and 80%, respectively. As the stone size increases, the need for additional sessions increases [953, 967, 968, 970-974]. Localisation of the calculi has been described as a significant factor affecting the success rates in different studies. Stones in the renal pelvis and upper ureter seem to respond better to SWL. For these locations, the stone clearance rates are nearly 90%. However, SWL was found to be less effective for caliceal stones; particularly the lower caliceal stones. Several studies reported stone-free rates for isolated lower caliceal stones varying between 50% and 62% [975-977]. Shockwave lithotripsy can also be used to treat ureteral calculi. However, this is a more specific issue and controversial. The success rates with SWL are less for distal ureteric stones. There may also be technical problems with localisation and focusing of ureteric stones in children [976-979]. The type of machine used significantly influences success rates and complications. First-generation machines can deliver more energy to a larger focal zone, resulting in higher fragmentation rates in a single therapy. However, general anaesthesia is usually required due to the intolerable discomfort associated with a first-generation machine. Later-generation machines have a smaller focal zone and deliver less energy, and have a lower risk of pulmonary trauma, however, additional treatments may be needed. The success rate is higher in younger children [972]. Although stenting does not affect stone clearance, overall complication rates are higher and hospital stay is longer in the unstented patient [972, 974]. Stenting is essential in solitary kidneys undergoing SWL treatment. Children with a large stone burden have a high risk of developing Steinstrasse and urinary obstruction and should be followed more closely for the risk of prolonged urinary tract obstruction after SWL. Post-SWL stent or nephrostomy tube placement may be needed in prolonged obstruction [940, 971]. The Hounsfield Unit (HU) of stone on non-contrast tomography has also been shown to be a predictive factor for success in children and SWL was found to be more successful in stones with HU less than 600 [958] and 1,000 [980]. Two nomogram studies revealed male gender, younger age, smaller stone size, single stone, non-lower pole localisation and negative history for previous intervention are favourable factors for stone clearance in paediatric SWL [981, 982]. A recent comparative study reported that these two nomograms are independent predictors of stone-free rate following SWL in paediatric patients [983]. Although, the invention of miniaturised endoscopic instruments seems to reduce the importance and popularity of SWL, it has the advantage of not carrying the risk of certain complications related to endoscopic surgeries and moreover studies comparing SWL and RIRS showed that besides having similar stone-free rates, SWL was cheaper, had shorter hospital stay [984],with less post-operative emergency visit, pain and anaesthetic session [985]. Complications arising from SWL in children are usually self-limiting and transient. The most common are: • renal colic; • transient hydronephrosis; • dermal ecchymosis; • UTI; • formation of Steinstrasse; • sepsis; • rarely, haemoptysis.

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In children with sterile pre-operative urine cultures, antibiotic prophylaxis to decrease infectious complications is not recommended [986]. However, every effort should be made to sterilise the urine before performing SWL, ureteroscopy (URS), or percutaneous nephrolithotomy (PCNL). Due to the smaller size of the probes, laser energy is easier to use in smaller instruments and is more useful for paediatric cases [987-996]. 3.15.4.2 Percutaneous nephrolithotomy Shockwave lithotripsy is the first choice for treating most renal paediatric stones. However, percutaneous renal surgery should be used for larger and complex stones. Pre-operative evaluation, indication and surgical technique are similar in children and adults. In most cases, percutaneous nephrolithotomy (PCNL) is used as monotherapy, but is also used as an adjunctive procedure to other therapies. The use of adult-sized instruments, in association with an increased number of tracts and sheath size, seems to increase blood loss. However, the development of small-calibre instruments means that PCNL can be used in children. In children (particularly smaller children), PCNL has some advantages, such as smaller skin incision, single-step dilation and sheath placement, good working access for paediatric instruments, variable length, and lower cost [986, 997, 998]. As monotherapy, PCNL is considerably effective and safe. The reported stone-free rates in the recent literature are between 86.9% and 98.5% after a single session. These rates increase with adjunctive measures, such as second-look PCNL, SWL and URS. Even in complete staghorn cases, a clearance rate of 89% has been achieved following a single session [990, 999-1003]. The most frequently reported complications of PCNL in children are bleeding, post-operative fever or infection, and persistent urinary leakage. Bleeding requiring transfusion in the modern series is reported in less than 10% [1004-1009] and is closely associated with stone burden, operative time, sheath size and the number of tracts [1008, 1010, 1011]. In recent studies, post-operative infectious complications, such as fever with or without documented UTI, are reported as less than 15% [1004, 1005, 1007-1009, 1012] and the origin of fever is not always found to be the infection. With the availability of smaller size instruments, miniaturised PCNL (‘miniperc’) through a 13F or 14F sheath [998, 1012, 1013] as well as ultramini-PCNL (UMP) through 12F sheaths [1014] have become possible, with decreased transfusion rates [1012]. The mini- and superminiPCNL (SMP) were shown to have higher efficacy with acceptable complication rates which were deemed to be a safe alternative to SWL by some authors [1015, 1016]. The SMP was shown to be advantageous over mini-PCNL in terms of complications with similar stone-free rates [1017, 1018]. This miniaturisation has been further developed into the technique of ‘micro-perc’ using a 4.85F ‘all-seeing needle’. This technique is still experimental and enables the stone to be fragmented by a laser in situ and left for spontaneous passage [1019]. A study revealed that microperc provides a similar stone-free rate with similar complication rates and a lower additional treatment rate compared with SWL in the treatment of kidney stone disease in children [1020] (LE: 3). For stones 10-20 mm, micro-PNL was shown to have comparable results, with less bleeding, compared to mini-PCNL [1021] and similar outcomes with less anaesthetic sessions compared to RIRS [1022] (LE: 3). As experience has accumulated in adult cases, new approaches have started to be applied in children, including tubeless PCNL. This technique has been used in uncomplicated surgery for stones < 2 cm, with patients left either with an indwelling catheter or double J stent in the ureter [1006, 1023] or totally tubeless [1024]. Moreover, use of US for establishment of access is gaining popularity [1025, 1026] and supine approach [1027] was also reported to be feasible in children. The mean post-operative hospital stay is similar to adults. It is reported as three to four days in all published literature and is much shorter than open surgery. The less invasive nature of this technique has made it a promising alternative to open surgery for treating renal stones in children (LE: 2) [1004, 1006, 1007, 10091011, 1013, 1014, 1019-1021, 1023, 1024, 1027, 1028]. 3.15.4.3 Ureterorenoscopy The increasing availability of smaller size endourological equipment has made it possible to manage paediatric ureteral stones using endoscopic techniques. The technique used in children is similar to the one used in adults. It is strongly recommended that guide wires are used and the procedure is performed using direct vision. Routine balloon dilation of the ureterovesical junction and ureteral stenting are controversial. In general, ureteric dilatation is being performed less and only in selected cases. There is a tendency to use hydrodilation more because it is similarly effective [986, 988, 994, 1029-1032] (LE: 3). Different lithotripsy techniques, including ultrasonic, pneumatic and laser lithotripsy, have all been shown to be safe and effective. Due to the smaller size of the probes, laser energy is easier to use in smaller instruments and is more useful for paediatric cases [987-996].

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All studies reporting the use of endoscopy for ureteric stones in children have clearly demonstrated that there is no significant risk of ureteric strictures or reflux with this mode of therapy (LE: 1). The risk of post-operative hydronephrosis depends on the presence of impacted stone and ureteral injury during operation [1033]. A multi-institutional study on the use of semi-rigid ureteroscopy for ureteral calculi in children has revealed that the procedure is effective with a 90% stone-free rate and efficacy quotient. The study also focused on the factors affecting the complication rates. The authors found that, although operating time, age, institutional experience, orifice dilation, stenting and stone burden were significant on univariate analysis, multivariate analysis revealed that operating time was the only significant parameter affecting the complication rate [1034]. However, for proximal ureteral stones semi-rigid ureteroscopy is not a good first option because of higher complication and failure rates [1035]. A recent literature review contains a growing number of case series on the use of flexible ureterorenoscopic interventions in children. Both intrarenal and ureteric stones can be treated using this approach [1036-1041]. In these series, the authors generally did not use active orifice dilation, but attempted to use a ureteral sheath where possible. However, an important problem was the inability to obtain retrograde access to the ureter in approximately half of the cases [1037, 1039]. This problem can be overcome by stenting and leaving the stent indwelling for passive dilation of the orifice, and performing the procedure in a second session. The success rates varied between 60 and 100%, with a negligible number of complications [1036, 1038-1040, 1042]. The need for additional procedures was related to stone size [1040]. A comparative study showed that retrograde intra-renal surgery (RIRS) had similar stone-free rate compared to ESWL after three months, with fewer sessions [1043], however for stones larger than 2 cm, RIRS monotherapy has lower stonefree rates than mini-PCNL with the advantages of decreased radiation exposure, fewer complications and shorter hospital stay [1044] (LE: 3). In contrast, for stones between 10-20 mm, RIRS has similar success and complication rates and shorter hospital stay and low radiation exposure when compared to micro-PNL [1045] (LE: 3). A recent systematic review revealed that compared with the other two treatments, PCNL had a longer operative time, fluoroscopy time and hospital stay. Shockwave lithotripsy had a shorter hospital stay, higher retreatment rate and auxiliary rate in comparison with the other two treatments. It was also shown that PCNL presented a higher efficacy quotient than the other two treatments, and RIRS had a lower efficiency than SWL and PCNL. In the subgroup analysis of paediatric patients with stone ≤ 20 mm, the comparative results were similar to those described above, except for the higher complication rate of PCNL than SWL [1046]. 3.15.4.4 Open or laparoscopic stone surgery Most stones in children can be managed by SWL and endoscopic techniques. However, in some situations, open surgery is inevitable. Good candidates for open stone surgery include very young children with large stones and/or a congenitally obstructed system, which also require surgical correction. Open surgery is also necessary in children with severe orthopaedic deformities that limit positioning for endoscopic procedures. In centres with a well-established experience, a laparoscopic approach may be a good alternative for some cases as a last resort before open surgery. Suitable candidates include patients who have a history of previous failed endoscopic procedures, complex renal anatomy (ectopic or retrorenal colon), concomitant UPJ obstruction or caliceal diverticula, mega-ureter, or large impacted stones. Laparoscopic stone surgery via conventional or a robot-assisted transperitoneal or retroperitoneal approach can be attempted. However, there is limited experience with these techniques and they are not routine therapeutic modalities [1047-1050]. Bladder stones in children can usually be managed by endoscopic techniques. Open surgery may also be used for very large bladder stones or for bladder stones caused by an anatomical problem. In addition to the advantages and disadvantages of each treatment modality for the specific size and location of the stone, consideration has to be given to the availability of the instruments and the experience with each treatment modality before the choice of technique is made. Recommendations for interventional management are given in Table 4.

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Table 4: Recommendations for interventional management in paediatric stones Stone size and localisation* Staghorn stones

Pelvis < 10 mm Pelvis 10-20 mm

Pelvis > 20 mm Lower pole calyx < 10 mm Lower pole calyx > 10 mm Upper ureteric stones Lower ureteric stones Bladder stones Bladder stones

Primary treatment Secondary treatment Comment option options PCNL Open/SWL Multiple sessions and accesses with PCNL may be needed. Combination with SWL may be useful. SWL RIRS/PCNL/MicroPerc SWL PCNL/RIRS/ Multiple sessions with SWL may be needed. PCNL has similar recommendation grade. PCNL MicroPerc/Open Multiple sessions with SWL may be needed. PCNL SWL/Open Multiple sessions with SWL may be needed. SWL SWL/Open Anatomical variations are important for complete clearance after SWL. SWL RIRS/PCNL/MicroPerc Anatomical variations are important for complete clearance after SWL. PCNL RIRS/PCNL/MicroPerc Anatomical variations are important for complete clearance after SWL. SWL SWL/ MicroPerc URS

PCNL/URS/Open

Endoscopic

SWL/Open

Endoscopic

Additional intervention need is high with SWL. Open is easier and with less operative time with large stones. Open is easier and with less operative time with large stones.

* Cystine and uric acid stones excluded. PCNL = percutaneous nephrolithotomy; SWL = shockwave lithotripsy; RIRS = retrograde intrarenal surgery; URS = ureteroscopy.

3.15.5

Summary of evidence and recommendations for the management of urinary stones

Summary of evidence The incidence of stone disease in children is increasing. Contemporary surgical treatment is based on minimally invasive modalities. Open surgery is very rarely indicated. The term ‘clinically insignificant residual fragments’ is not appropriate for children since most of them become symptomatic and require intervention.

Recommendations Use plain abdominal X-ray and ultrasound as the primary imaging techniques for the diagnosis and follow-up of stones. Use low-dose non-contrast computed tomography in cases with a doubtful diagnosis, especially of ureteral stones or complex cases requiring surgery. Perform a metabolic evaluation in any child with urinary stone disease. Any kind of interventional treatment should be supported with medical treatment for the underlying metabolic abnormality, if detected. Limit open surgery under circumstances in which the child is very young with large stones, in association with congenital problems requiring surgical correction and/or with severe orthopaedic deformities that limit positioning for endoscopic procedures.

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LE 2 2a 2b

LE 2b

Strength rating Strong

2a

Strong

2a

Strong

2a

Strong

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3.16

Obstructive pathology of renal duplication: ureterocele and ectopic ureter

3.16.1 Epidemiology, aetiology and pathophysiology Ureterocele and ectopic ureter are the two main anomalies associated with complete renal duplication, but they also occur in a single system. At present, antenatal US detects both conditions in the majority of cases if associated with obstruction, and diagnosis is confirmed after birth by further examination. Later in life, these anomalies are revealed by clinical symptoms: UTI, pain, calculus formation, disturbances of micturition, and urinary incontinence. There is a wide variation of symptoms in patients with ureterocele (from the asymptomatic patient to urosepsis, urinary retention and upper tract dilatation after birth). 3.16.1.1 Ureterocele Ureterocele is four to seven times more frequent in female than in male patients; the overall incidence in autopsies is around one in 4,000 children. Around 80% is associated with the upper pole ureter in duplicated systems and 20% in single systems. About 10% of ureteroceles are bilateral [1051]. 3.16.1.2 Ectopic ureter Ectopic ureter is less frequent than ureterocele (10 in 19,046 autopsies), but is also more common in female patients (male to female ratio is 1:5). Some remain asymptomatic, therefore, the true incidence is difficult to determine [1052]. Eighty per cent of ectopic ureters are associated with complete renal duplication; however, in male patients about 50% of ectopic ureters are associated with a single system [1053]. 3.16.2 Classification systems 3.16.2.1 Ureterocele Ureterocele is a cystic dilatation that develops in the intravesical part of the submucosal ureter. The aetiology remains unclear [1054-1056]. A single-system ureterocele is associated with a kidney with one ureter, and in duplex systems, the ureterocele belongs to the upper pole. Ureteroceles usually cause obstruction of the upper pole, but the degree of obstruction and functional impairment is variable according to the type of ureterocele and upper pole dysplasia. In the orthotopic form, there is often no or only mild obstruction, and frequently the function of the moiety is normal or slightly impaired, and the corresponding ureter may be dilated. Cystic renal dysplasia is also associated with a single system ureterocele [1057]. Vesicoureteral reflux can be observed in 50% on the ipsilateral side and 20% on the contralateral side. Reflux into the ureterocele is uncommon [1058]. In the ectopic form, the upper pole is altered, frequently dysplastic, and hypo-functional or non-functional [1059]. The corresponding ureter is a mega-ureter. In the caeco-ureterocele (see definition below), the upper pole of the renal duplication is dysplastic and non-functional. Histological evaluation demonstrated that the changes represent a process of maldevelopment and may not result from infections or obstruction [1059]. 3.16.2.1.1 Ectopic (extravesical) ureterocele If any portion of the ureterocele extends into the bladder neck or urethra, it is called an ectopic ureterocele. Ectopic ureterocele is the most common form of ureterocele (> 80%). It can be voluminous, dissociating the trigone and slipping into the urethra, and may prolapse through the urethral meatus (caeco-ureterocele). The ureterocele orifice is tight, and located in the bladder itself or below the neck. The ureter corresponding to the lower pole moiety is raised by the ureterocele and is frequently refluxing or compressed by the ureterocele, leading to an obstructive mega-ureter. A contralateral renal duplication is associated with 50% of cases. Occasionally, large ureteroceles are responsible for reflux or obstruction of the contralateral upper tract. 3.16.2.1.2 Orthotopic (intravesical) ureterocele The intravesical or orthotopic ureterocele is completely located in the bladder. Intravesical ureteroceles are mostly combined with a single kidney system and account for about 15% of cases. It is diagnosed more in older children or adults. 3.16.2.2 Ectopic ureter The term ectopic ureter describes a ureter with the orifice located at the bladder neck, in the urethra or outside the urinary tract. The ureter can drain the upper pole of a duplex or single system. There is a fundamental difference between the sexes. In boys, the ectopic orifice is never below the external sphincter. In girls, the ureteral orifice may be located [1060]: • in the urethra, from the bladder neck to the meatus (35%); • in the vaginal vestibule (34%); • in the vagina (25%); • in the uterus and Fallopian tube (6%).

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In boys, the ureteral orifice may be located [1060]: • in the posterior urethra (47%); • in the prostatic utricle (10%); • in the seminal vesicles (33%); • in the vas deferens or ejaculatory ducts (10%). 3.16.3 Diagnostic evaluation 3.16.3.1 Ureterocele Prenatal US easily reveals voluminous obstructive ureteroceles [1061]. In cases with a small upper pole or a slightly obstructive ureterocele, prenatal diagnosis is difficult. If prenatal diagnosis is impossible, the following clinical symptoms, besides incidental findings, can reveal the congenital anomaly at birth or later: • At birth, a prolapsed and sometimes strangulated ureterocele may be observed in front of the urethral orifice. In a newborn boy, it might cause acute urinary retention, simulating urethral valves. • The early symptom of pyelonephritis in either sex may lead to the diagnosis. • Later symptoms can include dysuria, recurrent cystitis and urgency. In cases of prenatal diagnosis, at birth US confirms the ureteral dilatation that ends at the upper pole of a renal duplication. It also demonstrates the presence of a ureterocele in the bladder, with a dilated ureter behind the bladder. At this point, it is important to assess the function of the upper pole using nuclear renography of the region of interest. This is best assessed with DMSA, however this requires a careful systematic review of the images [1062]. Magnetic resonance urography may visualise the morphological status of the upper pole and lower moieties and of the contralateral kidney as well as it can detect renal scars [1063, 1064]. Using functional MR urography, differential renal function can be assessed with low intra- and interobserver variability [1065]. Based on the prevalence of high-grade reflux, VCUG is mandatory for identifying ipsilateral or contralateral reflux and assessing the degree of intra-urethral prolapse of the ureterocele [1066]. Urethrocystoscopy may reveal the pathology in cases where it is difficult to make the differential diagnosis between ureterocele and ectopic mega-ureter. 3.16.3.2 Ectopic ureter Most of the ectopic mega-ureters are diagnosed primarily by US. In some cases, clinical symptoms can lead to diagnosis: • In neonates: dribbling of urine, pyuria, and acute pyelonephritis. • In young girls: permanent urinary incontinence besides normal voiding, or significant vaginal discharge as the equivalent of incontinence; an ectopic orifice may be found in the meatal region [1067]. • In pre-adolescent boys: epididymitis is the usual clinical presentation and the seminal vesicle may be palpable. Ultrasound, radionuclide studies (DMSA, VCUG, MR urography, high-resolution MRI, and cystoscopy) are the diagnostic tools to assess function, to detect reflux and rule out ipsilateral compression of the lower pole and urethral obstruction [1068]. In some cases, the large ectopic ureter presses against the bladder and can look like a pseudo-ureterocele [1069]. Girls who present with life-long minimal urinary incontinence, never being dry, normal bladder function, complete emptying, and normal US are very suspicious for ectopic ureter. This needs to be excluded or confirmed by MRI as it is the most sensitive method [1070]. 3.16.4 Management 3.16.4.1 Ureterocele Management is controversial with a choice between a non-operative approach, endoscopic decompression, ureteral re-implantation, partial nephroureterectomy, or complete primary reconstruction [1071-1076]. The choice of a therapeutic modality depends on the following criteria: clinical status of the patient (e.g. urosepsis); patient age; function of the upper pole; presence of reflux or obstruction of the ipsilateral or contralateral ureter; presence of bladder neck obstruction caused by ureterocele; intravesical or ectopic ureterocele; and caregivers’ and the surgeon’s preferences [1076]. When the diagnosis is made by US, prophylactic antibiotic treatment maybe indicated until a VCUG is performed. 3.16.4.1.1 Early treatment In the presence of febrile infection or obstruction at the bladder neck, immediate endoscopic incision or puncture of the ureterocele is recommended. In a clinically asymptomatic child with a ureterocele and a non

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or hypofunctional upper pole, without significant obstruction of the lower pole and without bladder outlet obstruction, prophylactic antibiotic treatment is given until follow-up procedures are instigated. Decompression of the dilated system facilitates later reconstructive surgery [1077, 1078]. 3.16.4.1.2 Re-evaluation Conservative treatment may be adopted in asymptomatic patients without any bladder outlet obstruction, severe hydroureteronephrosis of the ureterocele moiety or high-grade (over grade III) reflux [1076, 1079]. A meta-analysis showed that, after primary ureterocele-incision, the re-operation rate is higher in those with an ectopic ureterocele compared to those with an intravesical ureterocele [1072]. Secondary surgery is necessary if decompression is not effective, significant reflux is present, or there is obstruction of the ipsi- or contralateral ureters, and/or bladder neck obstruction or retained ureterocele [1080]. Surgery may vary from upper pole nephrectomy to complete unilateral LUT reconstruction [1075, 1081-1083]. In an ectopic ureterocele with severe hydroureteronephrosis and without reflux, the primary upper tract approach without endoscopic decompression (partial upper-pole nephroureterectomy, pyelo/ureteropyelo/ ureterostomy and upper-pole ureterectomy) has an 80% chance of being the definitive treatment [1076, 1084]. Also a LUT approach in those with a poorly or non-functioning upper pole is an option [1085]. Today, despite successful surgery, some authors think, that surgery may not be necessary at all in some patients [1086], as less aggressive surgical treatment and non-operative management over time can achieve the same functional results [1087]. Figure 11: A  lgorithm for the management of duplex system ureteroceles after the first 3-6 months of life [974] DSU

Asymptomatic No severe HUN or obstruction

No VUR

Symptomatic or severe HUN or obstruction

VUR

Low grade

Observation

VUR

Good function

High grade or multiple infections

Bladder surgery or endoscopic management

No VUR

Ectopic: upper to lower tract anastomosis

Intravesical endoscopic decompression

No/poor function

Ectopic UPPN

DSU = duplex system ureterocele; HUN = hydroureteronephrosis; UPPN = upper pole partial nephrectomy; VUR = vesicoureteric reflux to the lower pole. Obstruction is considered to be the presence of non-refluxing dilatation of non-ureterocele-bearing moieties (especially of the lower pole) or of an obstructive drainage pattern on diuretic renography. 3.16.4.2 Ectopic ureter In the majority of cases, the upper pole is dysplastic and poorly functioning. There are a variety of therapeutic options, each with its advantages and disadvantages. In non-functioning moieties with recurrent infections, heminephro-ureterectomy is a definite solution. Ureteral reconstruction (ureteral re-implantation/ ureteroureterostomy/ureteropyelostomy and upper-pole ureterectomy) are other therapeutic options especially in cases in which the upper pole has function worth preserving. These procedures can be performed through an open laparoscopic or robotic assisted approach [1088-1091]. So far there is no superior approach [1092]. In patients with bilateral single ectopic ureters (a very rare condition), an individual approach depending on the sex and renal and bladder function of the patient is necessary. Usually the bladder neck is insufficient in these patients [1093].

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3.16.5

Summary of evidence and recommendations for the management of obstructive pathology of renal duplication: ureterocele and ectopic ureter

Summary of evidence Ureterocele and ectopic ureter are associated with complete renal duplication, but they also occur in a single system. In most cases, in young children (first years of life) diagnosis is done by US. In older children clinical symptoms will prompt assessment. Management includes a conservative approach, endoscopic decompression, partial nephroureterectomy, or complete primary reconstruction. Choice of treatment will depend on: • clinical status of the patient (e.g., urosepsis); • patient age; • function of the upper pole; • presence of reflux or obstruction of the ipsilateral or contralateral ureter; • presence of bladder neck obstruction caused by ureterocele; • intravesical or ectopic ureterocele; Recommendations Ureterocele Diagnosis Use ultrasound (US), radionuclide studies (mercaptoacetyltriglycine (MAG3)/dimercaptosuccinic acid (DMSA)), voiding cystourethrography (VCUG), magnetic resonance urography, high-resolution magnetic resonance imaging (MRI), and cystoscopy to assess function, to detect reflux and rule out ipsilateral compression of the lower pole and urethral obstruction. Treatment Select treatment based on symptoms, function and reflux as well on surgical and parenteral choices: observation, endoscopic decompression, ureteral re-implantation, partial nephroureteretomy, complete primary reconstruction. Offer, early endoscopic decompression to patients with an obstructing ureterocele. Ectopic ureter Diagnosis Use US, DMSA scan, VCUG or MRI for a definitive diagnosis. Treatment Treatment In non-functioning moieties with recurrent infections, heminephro-ureterectomy is a definitive solution. Ureteral reconstruction (ureteral re-implantation/ureteroureterostomy/ ureteropyelostomy and upperpole ureterectomy) are other therapeutic option especially in cases in which the upper pole has function worth preserving.

3.17

LE 1 1 1 3

LE 3

Strength rating Weak

3

Weak

3

Weak

3

Weak

Disorders of sex development

3.17.1 Introduction The formerly called ‘intersex disorders’ were the subject of a consensus document in which it was decided that the term ‘intersex’ should be changed to ‘disorders of sex development’ (DSD) [1094]. The new classification has arisen due to advances in knowledge of the molecular genetic causes of abnormal sexual development, controversies inherent to clinical management and ethical issues. Controversial and negative terminology, e.g. ‘pseudohermaphroditism’ and ‘hermaphroditism’, have been renamed according to the new pathophysiological insights. Furthermore, some conditions presenting with severe male genital malformation, such as penile agenesis and cloacal exstrophy, which could not be categorised, have also been included. The term ‘disorders of sex development’ is proposed to indicate congenital conditions with atypical development of chromosomal, gonadal or anatomical sex. In addition, in 2017, the Parliamentary Assembly of the Council of Europe decided on a resolution called: “Promoting the human rights of and eliminating discrimination against intersex people” [1095]. The Parliamentary Assembly concluded that the majority of intersex people are physically healthy and only a few

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suffer from medical conditions that put their health at risk. Furthermore, they state that the prevailing medical view has been that intersex children’s bodies can and should be made to conform to either a male or a female paradigm, often through surgical and/or hormonal intervention and that this should be done as early as possible and that the children should then be raised in the gender corresponding to the sex assigned to their body. The Parliamentary Assembly considers that this approach involves serious breaches of physical integrity, in many cases concerning very young children or infants who are unable to give consent and whose gender identity is unknown. Therefore the Parliamentary Assembly called on Council of Europe member states with regard to effectively protecting children’s right to physical integrity and bodily autonomy and to empowering intersex people as regards the following rights: medically unnecessary sex-“normalising” surgery, sterilisation and other treatments practised on intersex children without their informed consent should be prohibited and in addition that it has to be ensured that, except in cases where the life of the child is at immediate risk, any treatment that seeks to alter the sex characteristics of the child, including their gonads, genitals or internal sex organs, is deferred until such time as the child is able to participate in the decision, based on the right to selfdetermination and on the principle of free and informed consent. The Panel refers to the consensus documents mentioned above as well as on the Parliamentary Assembly resolution. This chapter will focus on what is relevant for the practising paediatric urologist as the urologist is likely to be involved in neonates with DSD conditions. Overall, evidence-based literature on DSD is sparse. There are no RCTs and most studies are based on retrospective clinical descriptive studies or on expert opinion. An exception is the risk of gonadal cancer, for which the level of evidence is higher [1096]. Disorders of sex development can present as prenatal diagnosis, neonatal diagnosis and late diagnosis. Prenatal diagnosis can be based on karyotype or US findings; neonatal diagnosis is based on genital ambiguity and late diagnosis is made on early or delayed puberty. In this guideline, focus is on the neonatal presentation where the paediatric urologist plays a major role. For late diagnosis we refer to endocrinology and gynaecology guidelines on precocious and delayed puberty where paediatric urologists play a minor role [1097, 1098]. Dealing with neonates with DSD requires a multidisciplinary approach, which should include geneticists, neonatologists, paediatric and adult endocrinologists, gynaecologists, psychologists, ethicists and social workers. Each team member should be specialised in DSD and a team should have treated enough patients to ensure experience. 3.17.2 Current classification of DSD conditions Since the International Consensus Conference on intersex and its subsequent publications on classification of the various conditions of DSD, several updates have been published with the latest published by the Global DSD Update Consortium in 2016 [1099]. As the field of DSD is continuously developing and knowledge and viewpoints change over time, an effort was made to include representatives from a broad perspective including support and advocacy groups with the goal to focus patient care upon the best possible QoL. According to the international consensus in 2005, DSDs were defined as congenital conditions within which the development of chromosomal, gonadal and anatomic sex is atypical. The changes that were made according to terminology are as follows: 46XX DSD group formerly called female pseudohermaphrodite, over-virilisation of an XX female, and masculinisation of an XX female. In this group the vast majority is due to classic congenital adrenal hyperplasia (CAH) with various degrees of masculinisation. Among all DSD conditions together, 46XX CAH patients comprise approximately 80%. These conditions are extremely important since they can be potentially life threatening after birth because of salt loss phenomenon and immediate medical care is mandatory. 46XY DSD group in the past named male pseudohermaphrodite, undervirilisation of an XY male, and undermasculinisation of an XY male. This group is often quite heterogenous and includes the partial androgen insensitivity syndrome (PAIS) as well as the complete androgen insensitivity syndrome (CAIS) formerly called testicular feminisation..

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Sex chromosome mosaicism DSD group (45X, 45X/46XY, 47XXY) consists of multiple variants with the mixed gonadal dysgenesis being the most important one. Many have a normal male phenotype and others asymmetric genitalia. One scrotal half often contains a gonad which is likely to be a testis whereas the other side is more a labia majora with usually no palpable gonad, most likely to be a streak gonad. Ovotesticular DSD group was in the past called true hermaphrodite because of the presence of ovarian and testicular tissue in the same individual meaning that both – female and male structures – live together. There is great variability in phenotype with uni- or bilateral undescended gonads which can present as one ovary and one testis or as one or two ovotestes. Non-hormonal/non-chromosomal DSD group was introduced as well, including newborns with cloacal exstrophy where bladder and intestines are exposed, patients with aphallia, and severe micropenis. The latter one is a normally formed penis with a stretched length of < 2.5 standard deviation below the mean [1094, 1100]. Micropenis should be distinguished from buried and webbed penis, which are usually of normal size. The length of the penis is measured on the dorsal aspect, while stretching the penis, from the pubic symphysis to the tip of the glans [1094]. 3.17.3 Diagnostic evaluation 3.17.3.1 The neonatal emergency The first step is to recognise the possibility of DSD (Table 5) and to refer the newborn baby immediately to a tertiary paediatric centre, fully equipped with neonatal, genetics, endocrinology and paediatric urology units. Diagnosis of a 46XX DSD due to congenital adrenal hyperplasia should not be delayed and represents a neonatal emergency situation since the possibility of salt loss phenomenon can be fatal. Table 5: F  indings in a newborn suggesting the possibility of DSD (adapted from the American Academy of Pediatrics) Apparent male Severe hypospadias associated with bifid scrotum Undescended testis/testes with hypospadias Bilateral non-palpable testes in a full-term apparently male infant Apparent female Clitoral hypertrophy of any degree, non-palpable gonads Vulva with single opening Indeterminate Ambiguous genitalia 3.17.3.2 Family history and clinical examination A careful family history must be taken followed by a thorough clinical examination including various laboratory tests and imaging modalities (Table 6). Table 6: Diagnostic work-up of neonates with disorders of sex development History (family, maternal, neonatal) Parental consanguinity Previous DSD or genital anomalies Previous neonatal deaths Primary amenorrhoea or infertility in other family members Maternal exposure to androgens Failure to thrive, vomiting, diarrhoea of the neonate Physical examination Pigmentation of genital and areolar area Hypospadias or urogenital sinus Size of phallus Palpable and/or symmetrical gonads Blood pressure

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Investigations Blood analysis: 17-hydroxyprogesterone, electrolytes, LH, FSH, TST, cortisol, ACTH Urine: adrenal steroids Karyotype Ultrasound Genitogram hCG stimulation test to confirm presence of testicular tissue Androgen-binding studies Endoscopy ACTH = adrenocorticotropic hormone; FSH = follicle-stimulating hormone; hCG = human chorionic gonadotropin; LH = luteinising hormone; TST = testosterone. A thorough clinical examination in a neonate presenting with ambiguous genitalia is important. As well as an accurate description of the ambiguous genitalia, detailed information should be given on palpability and localisation of the gonads. Information gathered by the various examinations described below should help the team to come to a final diagnosis. Medical photography can be useful but requires sensitivity and consent [1101]. Palpable gonad: If it is possible to feel a gonad, it is most likely to be a testis; this clinical finding therefore virtually excludes 46XX DSD. Phallus: The phallus should be measured. A cotton bud placed at the suprapubic base of the implant of the stretched phallus allows for a good measurement of phallic length. Urogenital sinus opening: The opening of the urogenital sinus must be well evaluated. A single opening has to be identified as well as a hymenal ring. Attention needs to be paid to the fusion of the labioscrotal folds as well as whether they show rugae or some discolouration. Ultrasound can help to describe the palpated gonads or to detect non-palpable gonads. However, the sensitivity and specificity are not high. Mülllerian structures like the vagina or utricular structures can be evaluated as well [1102, 1103]. Genitography can provide some more information on the urogenital sinus, especially on the exact position of the confluence. Moreover, it gives evidence of possible duplication of the vagina. Invasive diagnostics under general anaesthesia can be helpful in some cases. On cystoscopy, the urogenital sinus can be evaluated as well as the level of confluence. It allows also for evaluation of the vagina or utriculus, the possible presence of a cervix at the top of the vagina. Laparoscopy is necessary to obtain a final diagnosis on the presence of impalpable gonads and on the presence of Müllerian structures. If indicated, a gonadal biopsy can be performed [1104, 1105]. These investigations will help to distinguish the various conditions of DSD and provide quick evidence of congenital adrenal hyperplasia (CAH), which is the most frequently occurring DSD and the one that can become life-threatening within the first days of life because of salt loss phenomenon. 3.17.4 Gender assignment Nowadays it is obvious and clear that open and complete communications with caregivers and eventually the affected person are mandatory. Education and psychological support regarding the impact are needed for each individual to make sense of the condition, relate to their community and establish relationships. The lack of outcome data and different preferences make it extremely difficult to determine whether and when to pursue gonadal or genital surgery. Shared decision making is necessary, combining expert healthcare knowledge and the right of a patient or surrogate to make fully informed decisions. This entails a process of education, sharing of risks/benefits, articulating the uncertainties in DSD care and outcomes and providing time for the patient and family to articulate back the risks and benefits of each option. The goal of all involved should be to individualise and prioritise each patient. However, adverse outcomes have led to recommendations to delay unnecessary surgery to an age when the patient can give informed consent. Surgery that alters appearance is not urgent. Recently the Parliamentary Assembly of the Council of Europe, the European Society for Paediatric Urology (ESPU) as well as the Societies for Pediatric Urology have taken a position in the debate on surgery for DSD [1095, 1106, 1107]. PAEDIATRIC UROLOGY - LIMITED UPDATE MARCH 2021

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In an open letter to the Council of Europe, the European Society for Paediatric Urology expressed its attitude to the abovementioned resolution and concentrated on a worrying issue dealing with medicosurgical care for children with DSD. It states that surgical interventions in children with DSD only being applied in emergency conditions is discordant with the definition of health according to the World Health Organization (WHO), stating that health is not merely the absence of disease, but is a much broader concept, including physical, mental, and social domains. This especially applies to children, as favourable physical, social and emotional conditions are all critical factors for their optimal growth and development, which enables them to reach their full potential at adult age. As social and emotional interactions with the parents or caregivers, being the most important adults in a young child’s life, form the basis for their future, treatment of children with DSD can best be organised in a patient- and family-centred multidisciplinary setting, in an atmosphere based on openness, commitment and trust. Physicians, who daily take care of children with a variety of congenital conditions, the same as their parents or caregivers, are committed to the current as well as the future health and well-being of all children entrusted to their care. In contrast to what is alleged in the recommendation, parents and caregivers implicitly act in the best interest of their children and should be respected as their outstanding representatives, and should not be put aside by claiming prohibition regulations regarding the well-informed decisions they make on their behalf. Finally in that open letter the ESPU advocate keeping the dialogue open with the professionals active in specialised centres for multidisciplinary, patient- and familycentred care as well as with patient societies, for which the present resolution is recognised as being a solid starting base [1108]. 3.17.5 Risk of tumour development Individuals with DSD have an increased risk of developing cancers of the germ cell lineage, malignant germ cell tumours or germ cell cancer in comparison with to the general population [1109]. It is well-recognised that the highest risk prevalence (30-50%) is seen in conditions characterised by disturbed gonadal development such as incomplete testis development combined with a full block of embryonic germ cell maturation in patients with 46XY gonadal dysgenesis and in some patients with 45X/46XY DSDs. Conversely, patients with testosterone biosynthesis disorders and androgen action disturbances show a much lower risk (1-15%) for carcinoma in situ (CIS) development during childhood and a limited tendency towards invasive progression of the lesions [1110]. With regard to clinical management a gonadal biopsy at the time of a possible orchidopexy can be obtained for an initial assessment including regular self-exams and annual ultrasound [1096]. 3.17.6

Recommendations for the management of disorders of sex development

Recommendations Newborns with DSD conditions warrant a multidisciplinary team approach. Refer children to experienced centres where neonatology, paediatric endocrinology, paediatric urology, child psychology and transition to adult care are guaranteed. Do not delay diagnosis and treatment of any neonate presenting with ambiguous genitalia since salt-loss in a 46XX CAH girl can be fatal.

3.18

Strength rating Strong Strong Strong

Congenital lower urinary tract obstruction (CLUTO)

Introduction The term congenital lower urinary tract obstruction (CLUTO) is used for a foetus, which during intrauterine US screening shows a dilatation of the upper and lower urinary tract. During pregnancy the diagnosis is usually based only on US examinations. There is a broad spectrum of conditions, that could cause an intrauterine dilatation of the urinary tract. Post-partum diagnosis comprises any anatomical and functional disorder/ anomaly/malformation causing a dilatation e.g. posterior/anterior urethral valve, urethral atresia/dysplasia/ stenosis prune belly syndrome, dilating reflux. Cloacal malformation, ureterocele, a Megacystis-Microcolonintestinal hypoperistalsis or Megacystis-Megaureter Syndrome [1111-1114]. Megacystis In the first trimester, foetal megacystis is defined as a bladder with a longitudinal diameter ≥ 7 mm, and in the 2nd and 3rd trimester as an enlarged bladder failing to empty during an extended US examination lasting at least 40 minutes. Two thirds of cases are secondary to CLUTO and the remainder are associated with genetic syndromes, developmental or chromosomal abnormalities including anorectal malformations; 14% were normal or having isolated urological abnormality (e.g. VUR, Duplex system) [1115]. A more recent systematic review showed that at least 45% of cases have oligohydramnios and 15% have chromosomal abnormalities, most of them being trisomy 13, 18 and 21. Final diagnoses were posterior urethral valve (PUV) (57%), urethral atresia/stenosis (7%),

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prune-belly syndrome (4%), megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) (1%), cloacal abnormality (0.7%) and undefined pathologies (36.5%). Termination of pregnancy rate was 50% [1116]. The prognosis of the foetus depends on the underlying pathology, the timing of diagnosis, presence of an oligo-, anhydramnios and bladder volume. Fontanella et al developed a staging system of CLUTO. They described three groups: severe (Bladder volume ≥ 5.4 cm3 and/or oligo-, an hydramnios before 20 weeks), moderate (Bladder volume < 5.4 cm3 and/or normal amniotic fluid at 20 weeks) and mild (Normal AF at 26 weeks) [1117]. This staging system can be used to predict perinatal mortality and post-natal estimated GFR. Another recent systematic review on prognosis of megacystis patients revealed an overall intrauterine spontaneous resolution of 32%, with better resolution rates in early (before 18 weeks) megacystis cases (40% vs. 12%) [1118]. 3.18.1 Posterior urethral valves 3.18.1.1 Epidemiology, aetiology and pathophysiology Posterior urethral valves are one of the few life-threatening congenital anomalies of the urinary tract found during the neonatal period. A recent systematic review showed, that the risk for chronic kidney disease (CKD) could be up to 32% and for end-stage kidney disease (ESKD) up to 20% [1119]. Up to 17% of paediatric ESKD can be attributed to PUV [1120]. An incidence of PUV of 1 in 7,000-8,000 live-births has been estimated [1112, 1121]. 3.18.2 Classification systems 3.18.2.1 Urethral valve Up until today, the original classification by Hugh Hampton Young is the most commonly used classification [1122]. Hugh Hampton Young described three categories: type I, type II and type III. However, today, only type I and type III are found to be obstructive. As type II seems to be more like a fold and not obstructive, it is no longer referred to as a valve. Hampton Young’s descriptions of type I and III are as follows: Type I (90-95%). ‘In the most common type there is a ridge lying on the floor of the urethra, continuous with the verumontanum, which takes an anterior course and divides into two fork-like processes in the region of the bulbomembranous junction. These processes are continued as thin membranous sheets, direct upward and forward which may be attached to the urethra throughout its entire circumference. It is generally supposed that the valves have complete fusion anteriorly, leaving only an open channel at the posterior urethral wall. Yet, the fusion of the valves anteriorly may not be complete in all cases, and at this point a slight separation of the folds exists’ [1122]. Type III. ‘There is a third type which has been found at different levels of the posterior urethra and which apparently bears no such relation to the verumontanum. This obstruction was attached to the entire circumference of the urethra, with a small opening in the centre [1112]. The transverse membrane described has been attributed to incomplete dissolution from the urogenital portion of the cloacal membrane [1123]. The embryology of the urethral valves is poorly understood. The membrane may be an abnormal insertion of the mesonephric ducts into the foetal cloaca [1124]. 3.18.3 Diagnostic evaluation An obstruction above the level of the urethra affects the whole urinary tract to varying degrees. • The prostatic urethra is distended and the ejaculatory ducts may be dilated due to urinary reflux. • The bladder neck is hypertrophied and rigid. • The hypertrophied bladder occasionally has multiple diverticula. • Nearly all valve patients have dilatation of both upper urinary tracts. This may be due to the valve itself and the high pressure in the bladder, or due to obstruction of the ureterovesical junction by the hypertrophied bladder. • If there is secondary reflux, the affected kidney functions poorly in most cases. During prenatal US screening, bilateral hydroureteronephrosis and a distended bladder are suspicious signs of a urethral valve. A thick-walled bladder seems to be of better prediction of a PUV than a dilated posterior urethra (‘keyhole’ sign) [1125]. However, differentiation between obstructive and non-obstructive aetiologies on prenatal US is challenging as both have a similar US appearance [1126] In the presence of increased echogenicity of the kidney, dilatation of the urinary tract and oligohydramnion, the diagnosis of a PUV should strongly be considered. Prenatal US is adequate in most of the cases (90%) [1127]. However in some circumstances when technical US conditions are poor such as oligo- or anhydramnios, large maternal body habitus, unfavourable position of the foetus or in suspicion of complex foetal anomalies such as accompanying gastrointestinal system, foetal MRI may provide additional information [1127-1129]. Post-natally, a voiding cystourethrogram confirms the diagnosis of a PUV. This study is essential whenever there is a question of an infravesical obstruction, as the urethral anatomy is well-outlined during

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voiding. A secondary reflux is observed in at least 50% of patients with PUV [1130]. Reflux is consistently associated with renal dysplasia in patients with PUV. It is generally accepted that reflux in the renal units acts as a ‘pressure pop-off valve’, which would protect the other kidney, leading to a better prognosis [1131]. Other types of pop-off mechanisms include bladder diverticula and urinary extravasation, with or without urinary ascites [1132]. However, in the long-term, this supposed protective effect did not show a significant difference compared to other patients with PUV [1133, 1134]. Nuclear renography with split renal function is important to assess kidney function (DMSA or MAG3). Creatinine, blood urea nitrogen and electrolytes should be monitored closely during the first few days. Initial management includes a multi-disciplinary team involving a paediatric nephrologist. The clinician must be aware of a noteworthy association between PUV and undescended testes and/or inguinal hernia [1135]. Undescended testes occurred in 12-17% of PUV which is consistent with a 10-fold increase [1136]. 3.18.4 Management 3.18.4.1 Antenatal treatment Today most of PUV are discovered before birth [1111-1114]. The intrauterine obstruction leads to a decreased urine output, which could result in an oligo- or anhydramnios. Amniotic fluid is necessary for normal development of the lung and its absence may lead to pulmonary hypoplasia, causing a life-threatening problem. Kidneys start to produce urine at around 10th weeks of antenatal life. Many of the megacystis cases (7-15 mm) with normal karyotype spontaneously resolve before 20 weeks, whereas it is unlikely in those with a bladder length > 15mm (> 12mm before age of 18 Weeks of gestation) [1126, 1137, 1138]. Antenatal imaging of kidneys before 20 weeks is difficult and in rare instances imaging could be done earlier via transvaginal route [1139]. The possible spontaneous resolution chance of bladder enlargement and timing of proper kidney imaging are possibly the main obstacles on the optimum timing for prenatal intervention. As renal dysplasia is not reversible, it is important to identify those foetuses with good renal function. A sodium level below 100 mmol/L, a chloride value of < 90 mmol/L and an osmolarity below 200 mOsm/L found in three foetal urine samples gained on three different days are associated with a better prognosis [1140]. Urine samples before 23 weeks of gestation (ß2-microglobline, sodium, chloride and calcium) may be helpful to distinguish between those who could benefit from intrauterine therapy and those in whom the outcome is most likely to be compromised [1141]. The status of amniotic fluid, the appearance of the kidneys as well as the foetal urine biochemistry could be helpful in counselling the caregivers. Prenatal interventions aim to restore amniotic fluid volume and attenuate the risk of pulmonary hypoplasia or further renal damage [1142]. Decision for prenatal intervention can be based on a staging system that is composed of renal ultrasonographic findings, amnion amount and foetal urine biochemistry [1113]. Early intervention – before the age of 16 weeks of gestation, may be beneficial for the renal function, however making the correct diagnosis and the detection of other severe co-morbidties is extremly difficult at this time point [1143]. Later interventions are mostly of benefit for the lung development, but not for renal function. The placing of a vesicoamniotic shunt has a complication rate of 21-59% with dislocation of the shunt being the most common one [1142]. The PLUTO-trail (randomised study) failed to show any long-term benefit on renal function by placing a visual analogue scale (VAS) [1144]. A recent meta-analysis on interventions for CLUTO reported that VAS resulted in a higher perinatal survival rate than conservative management (57.1% vs 38.8%) with no significant differences in 6-12 month survival, 2-year survival or postnatal renal function [1145]. Foetal cystoscopy with laser ablation has a high complication rate without evidence for the effectiveness of these interventions [1146]. To avoid the severe complication of the laser ablation, balloon dilation is tried [1147]. The number of patients included and designs of these studies are insufficient to give any recommendations. Parental information is very important and the natural history of CLUTO including the postnatal outcomes with or without prenatal treatment as well as the uncertainties and/or controversies about CLUTO diagnosis and treatment should be discussed [1142]. 3.18.4.2 Postnatal treatment Bladder drainage. If a boy is born with suspected PUV, drainage of the bladder and, if possible, an immediate VCUG is necessary. A neonate can be catheterised with a small catheter without a balloon, preferably a feeding tube. A VCUG is performed to see if the diagnosis is correct and whether the catheter is within the bladder and not in the posterior urethra. An alternative option is to place a suprapubic catheter, perform a VCUG and leave the tube until the neonate is stable enough to perform an endoscopic incision or resection of the valve. Valve ablation. When the medical situation of the neonate has stabilised and the creatinine level decreased, the next step is to remove the intravesical obstruction. In cases where the urethra is too small to safely pass

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a small foetal cystoscope, a suprapubic diversion is performed until valve ablation can be performed. Small paediatric cystoscopes and resectoscopes are now available either to incise, ablate or to resect the valve at the 4-5, 7-8 or 12 o’clock position, or at all three positions, depending on the surgeon’s preference. It is important to avoid extensive electrocoagulation, as the most common complication of this procedure is stricture formation. Two studies demonstrated a lower urethral stricture rate using the cold knife compared to diathermy [1148, 1149]. Within the three months following initial treatment, effectiveness of the treatment should be demonstrated either by clinical improvement (US and renal function), control VCUG or a re-look cystoscopy, depending on the clinical course [1150-1152] . Vesicostomy. If the child is too small and/or too ill to undergo endoscopic surgery, a suprapubic diversion is performed to drain the bladder temporarily. If initially a suprapubic tube has been inserted, this can be left in place for six to twelve weeks. Otherwise, a cutaneous vesicostomy provides an improvement or stabilisation of the UUT in up tp 90% of cases [1153, 1154]. Although there has been concern that a vesicostomy could decrease bladder compliance or capacity, so far there are no valid data to support these expectations [1155, 1156]. Moreover, it was shown in PUV patients with stage 3 CKD that adding vesicostomy to valve ablation no long-term benefit was noted from diversion in the ultimate incidence of ESKD [1157]. High diversion. If bladder drainage is insufficient to drain the UUT, high urinary diversion should be considered. Diversion may be suitable if there are recurrent infections of the upper tract, no improvement in renal function and/or an increase in upper tract dilatation, despite adequate bladder drainage. The choice of urinary diversion depends on the surgeon’s preference for high-loop ureterostomy, ring ureterostomy, end ureterostomy or pyelostomy, with each technique having advantages and disadvantages [1158-1161]. Diversion can delay progression to end stage renal failure [1157]. Reconstructive surgery should be delayed until the UUT has improved as much as can be expected. Reflux is very common in PUV patients (up to 72%) and it is described bilaterally in up to 32% [1162]. During the first months of life, antibiotic prophylaxis may be given especially in those with high-grade reflux [876] and in those with a phimosis, circumcision can be discussed in order to reduce the risk of UTIs [1163]. However, there are no randomised studies to support this for patients with PUV. Early administration of oxybutynin may improve bladder function as shown in one study with eighteen patients [1164]. High-grade reflux is associated with a poor functioning kidney and is considered a poor prognostic factor [1165, 1166]. However, early removal of the renal unit seems to be unnecessary, as long as it causes no problems. Moreover, in the long term it may be necessary to augment the bladder and in this case the ureter may be used [1167]. Deterioration of renal function without a fixed obstruction and higher urine output (polyuria) may lead to an overdistension of the bladder during the night. Drainage of the bladder during the night by a catheter may be beneficial for the hydronephrosis as well as for renal function [1168, 1169]. Patients with high daytime PVR urine may benefit from CIC [1170, 1171]. In those who do not want or are not able to perform a CIC via urethra, the placement of a Mitrofanoff is a good alternative [1172]. 3.18.5 Follow-up Several prognostic factors have been described. Different serum nadir creatinine levels are given in the literature (0.85 mg/dl-1.2 mg/d (μmol/L) [1173-1176]. Renal parenchyma quantity (total renal parenchymal area) and quality (corticomedullary differentiation and renal echogenicity) on initial postnatal US also have prognostic value [1177]. Life-long monitoring of these patients is mandatory, as bladder dysfunction (‘valve bladder’) is not uncommon and the delay in day- and night-time continence is a major problem [1178, 1179]. The literature demonstrates that urodynamic studies plays an important role in the management of patients with valve bladder especially in those with suspicion of bladder dysfunction [1180, 1181]. Poor bladder sensation and compliance, detrusor instability and polyuria (especially at night) and their combination are responsible for bladder dysfunction. In those with bladder instability, anticholinergic therapy can improve bladder function. However, there is a low risk of reversible myogenic failure (3/37 patients in one study) [1182, 1183]. In patients with poor bladder emptying, α-blocker can be used to reduce the PVR urine, as demonstrated in one study with 42 patients using terazosin (mean PVR was reduced from 16 to 2 mL) [1184]; in another study tamsulosin was effective [1185]. Concerning bladder neck incision, there is no Panel consensus concerning indication and efficacy. High creatinine nadir (> 1 mg/dL) and severe bladder dysfunction are risk factors for renal replacement therapy [1186, 1187]. Renal transplantation in these patients can be performed safely and effectively [1188, 1189]. Deterioration of the graft function is mainly related to LUTD [1188]. Therefore, it is essential to have and keep a good reservoir function. An assessment and treatment algorithm is provided in Figure 12.

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There are only few reports on sexual function and fertility in patients with PUV demonstrating some impairment especially in those who are on dialysis [1190, 1191]. In a review the majority have good erectile function (7494%) and a fertility comparable to the normal population [1192]. However, a negative influence of the individual patient’s fertility has to be taken into account, as these patients have a higher risk for bilateral cryptorchidism, recurrent epididymitis and ESRD [1192]. Figure 12: An algorithm on the assessment, management and follow-up of newborns with possible PUV Newborn with possible PUV, UUT dilation and renal insufficiency

• USG and VCUG • Assesment of renal function and electrolyte disorders

Confirm diagnosis

Bladder drainage

No stabilisation

Nephrological care, if needed Valve ablation when infant is stable

Improvement in UT dilation and RF

No improvement but stable

• Close follow-up • Monitor urinary infection • Monitor renal function • Monitor night-time polyuria and bladder over-extension

• Progressive loss of renal function • Recurrent infections • Poor emptying

Long term

No improvement and ill

Consider diversion

Short term

• Check residual PUV • CIC if not emptying • Consider overnight drainage • Consider α-blockers • Anticholinergics if OAB

Consider augmentation and Mitrofanoff

CIC = clean intermittent catheterisation; OAB = overactive bladder; PUV = posterior urethral valve; RF = renal function; UT = urinary tract; UUT = upper urinary tract; VCUG = voiding cystourethrogram. 3.18.6 Summary Posterior urethral valves are one of the few life-threatening congenital anomalies of the urinary tract found during the neonatal period and despite optimal treatment result in renal insufficiency in nearly one-third of cases. Bilateral hydroureteronephrosis and a distended bladder are suspicious signs of a PUV in neonates. A VCUG confirms a PUV diagnosis. Nuclear renography with split renal function is important to assess kidney function and serum creatinine nadir above 80 μmol/L is correlated with a poor prognosis. Today, antenatal therapy is becoming more and more popular. Identification of those with an obstructive uropathy and definiton of those who would benefit from early antenatal intervention are the major challenges. Postnatal treatment

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includes bladder drainage, either transurethral or suprapubic and if the child is stable enough, endoscopic incision of the valve is performed. If a child is too small and/or too ill to undergo endoscopic surgery, a vesicostomy is an option for bladder drainage. If bladder drainage is insufficient to drain the UUT, high urinary diversion should be considered. In all patients life-long monitoring is mandatory, as bladder dysfunction is quite common and may cause progressive upper tract deterioration, if not managed properly. In the long-term between 10 and 47% of patients may develop end-stage renal failure. Renal transplantation in these patients can be performed safely and effectively. • Anterior urethral valve (AUV) Anterior urethral valve is a semilunar or iris-like band of tissue on ventral aspect of urethra. It can be isolated, in association with or confused with urethral diverticulum. The aetiology of isolated AUV is speculated to be secondary to congenital urethral obstruction, malunion of glanular and penile urethra, congenital cystic dilatation of peri-urethral glands or ruptured distal lip of a syringocele [1193]. Anterior urethral valve occurs less frequently than PUV. It can be present in the bulbous urethra, the penoscrotal junction and penile urethra. Patients may present with poor urinary stream, penile ballooning, UTI or haematuria. Anterior urethral valves have been classified by Firlit et al depending on the presence of diverticulum and the dilatation of urethra and upper tract [1194]. The diagnosis is based on VCUG with possible findings of dilated or elongated posterior urethra, a dilatation of the anterior urethra, a thickened trabeculated bladder, a hypertrophied bladder neck, VUR, and urethral diverticula. In doubtful cases, retrograde urethrography may be helpful showing linear filling defect along the ventral wall, or it may show a dilated urethra ending in a smooth bulge or an abrupt change in the caliber of the dilated urethra on VCUG [1195]. Treatment is performed mainly by endoscopic valve ablation. In selected patients, a temporary diversion may be considered until the child is big enough for endoscopy to be possible. Open surgery is reserved in patients with very large diverticulum and defective spongiosum. Renal failure may develop in 22% and the risk is highest in patients with pre-treatment azotaemia, VUR and UTI [1196]. • Anterior urethral diverticulum (AUD): Common postnatal presenting features of AUD are compressible ventral penile swelling, urinary dribble postmicturition, voiding difficulty, poor stream, and recurrent UTIs [1197-1199]. Diagnosis is made by VCUG with or without a retrograde urethrogram. In small AUD, endoscopic cutting or deroofing of distal lip of the diverticulum can be used as a treatment modality. Larger diverticulum requires excision of the diverticulum with a twolayered urethroplasty; or marsupialisation with staged urethroplasty. In cases of urosepsis and obstructive uropathy, a suprapubic catheter may be placed. Once the infant’s condition improves, temporary urinary diversion with vesicostomy or proximal cutaneous urethrostomy can be performed before definitive surgical management [1200, 1201]. The diverticulum is associated with a distal lip-like tissue which may be confused with a valve. Anatomically, AUV have normal corpus spongiosum development whereas AUD have incomplete spongious tissue formation [1200]. • Syringocele Cowper glands are two bulbourethral glands located within the urogenital diaphragm and secrete pre-ejaculatory mucus on both sides through the external sphincter into the urethra 1-2 cm distal to the sphincter. Syringocele is the cystic dilatation of these glands. The aetiology can be congenital (retention cyst of the intraurethral portion of the duct) or acquired (trauma or infection). It has been classified as simple, imperforate, perforate and ruptured [1202]. A simpler grouping is suggested to merge simple, perforate and ruptured into “open syringocele” and imperforate to “closed syringocele”. Closed syringoceles cause obstructive symptoms and open ones act as a diverticula and cause post-voiding drippling and sometimes obstruction due to orientation of one membrane into urethra [1203] . However, it is better to simply categorise into two groups as obstructing and non-obstructing in terms of understanding pathophysiology and management [1204]. Depending on the syringocele type, patients present with post-void dribbling, urethral discharge, UTI, perineal pain, haematuria, obstructive voiding symptoms, dysuria and retention. Diagnosis is based on antegrade and/ or retrograde urethrogram which shows a cystic defect distal to prostate. If the VUC/RGU are inconclusive, US and/or MRI may be used if open reconstruction is being planned. Endoscopic deroofing of the cyst in both obstructing and non-obstructing syringoceles is an effective method of marsupialisation [1205]. In cases where endoscopic approach is not feasible open correction may be considered. • Cobb’s collar Cobb’s collar is a congenital membranous stricture of the bulbar urethra. It is different from congenital obstructive posterior urethral membrane (COPUM) and is independent of the verumontanum and external sphincter and may represent a persistence of part of the urogenital membrane [1206]. Voiding cystourethrogram shows narrowing in the proximal bulbar urethra with folds extending proximally, a dilated

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posterior urethra, prominent bladder neck and other findings of infravesical obstruction. Treatment is an endoscopic incision; using cold-knife showed lower recurrence rates than electrocautery [1207]. • Urethral atresia/hypoplasia Male urethral atresia is a congenital, complete obstruction of the urethra caused by a membrane that is usually located at the distal end of the prostatic urethra. The urethra distal to this point is usually hypoplastic, presumably from lack of foetal voiding [1208]. Urethral atresia is associated with bladder distention, VUR, hydronephrosis and renal dysplasia [1209]. Most cases reported have the phenotypic characteristics of the prune belly syndrome. Antenatal intervention may be beneficial in terms of foetal survival [1210]. Although progressive augmentation by dilating the urethra anterior (PADUA) procedure was described as a treatment modality, the majority of cases requires some form of supravesical diversion [1208, 1209]. • Posterior Urethral Polyps: Although, posterior urethral polyps (PUP) does not cause antenatal hydronephrosis, it could cause obstruction later in life. Posterior Urethral Polyps is a polypoid, pedunculated, fibroepithelial lesion arising in posterior urethra proximal to the verumontanum. It lies on the floor of the urethra with its tip reaching into the bladder neck and obstruction occurs because of distal displacement of polyp during urination [1211]. Patients complain of dysuria, haematuria and obstructive symptoms such as poor urinary stream and intermittent retention episodes. Diagnosis can be suspected by VCUG and/or US but is confirmed during cystourethroscopy. Treatment is usually an endoscopic resection of the polyp. The course of the disease is benign and no recurrences were reported in the literature [1212, 1213]. 3.18.7

Summary of evidence and recommendations for the management of posterior urethral valves

Summary of evidence Posterior urethral valves are one of the few life-threatening congenital anomalies of the urinary tract found during the neonatal period. Antenatal therapy could be discussed based on ultrasound findings, fetal urine biochemistry amount of amnion fluid and chromosomal status. Despite optimal treatment nearly one-third of the patients end up in renal insufficiency. Bilateral hydroureteronephrosis and a distended bladder are suspicious signs on US; a VCUG confirms the diagnosis. Serum creatinine nadir above 85 μmol/L is correlated with a poor prognosis. In the long-term up to 20% of patients develop end-stage renal failure due to primary dysplasia and/ or further deterioration because of bladder dysfunction. Renal transplantation in these patients is safe and effective, if the bladder function is normalised. Recommendations Diagnose posterior urethral valves (PUV) initially by ultrasound but a voiding cystourethrogram (VCUG) is required to confirm the diagnosis. Assess split renal function by dimercaptosuccinic acid scan or mercaptoacetyltriglycine (MAG3) clearance. Use serum creatinine as a prognostic marker. Vesico-amniotic shunt antenatally is not recommended to improve renal outcome. Offer endoscopic valve ablation after bladder drainage and stabilisation of the child. Offer suprapubic diversion for bladder drainage if the child is too small for valve ablation. Offer a high urinary diversion if bladder drainage is insufficient to drain the upper urinary tract and the child remains unstable. Monitor bladder and renal function life-long, in all patients.

3.19

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Rare Conditions in Childhood

3.19.1 Urachal remnants 3.19.1.1 Introduction The urachus is an embryonic structure arising as a result of the separation of the allantois from the ventral cloaca. The allantois appears on day sixteen as a tiny, fingerlike outpouching from the caudal wall of the yolk sac, which is contiguous with the ventral cloaca at one end and the umbilicus at the other. The ventral portion of the cloaca develops into the bladder after cloacal division by the urogenital septum. Thus, the bladder initially extends all

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the way to the umbilicus [1214]. With progressive foetal development, as the bladder descends into the pelvis, the attachment between the umbilicus and the urachus becomes looser and the apical portion progressively narrows to a small, epithelialised, fibromuscular strand by the fourth or fifth month of gestation. The urachus then obliterates completely by birth, forming the median umbilical ligament [1215-1217]. The urachus varies from 3 to 10 cm in length and from 8 to 10 mm in diameter. It is a three-layered tubular structure, the innermost layer being lined with transitional epithelium, the middle layer composed of connective tissue, and the outermost muscular layer in continuity with the detrusor muscle [1218]. Urachal remnants (URs) originate from failure of the obliteration of the allantois, resulting in a urachal anomaly such as (1) urachal sinus, (2) urachal cyst, (3) vesico-urachal diverticulum, and (4) patent urachus [1215, 1216, 1219]. Most often the urachal anomaly is asymptomatic, but it occasionally may become infected, may cause urinary symptoms, or develop a urachal carcinoma in later life [1218, 1220]. 3.19.1.2 Epidemiology Reports of occurrence rates in the literature vary broadly from a very rare disease in the older literature to a fairly common problem. Robert et al. found that URs were present in 61.7% of patients younger than 16 years [1221]. They also noted that the frequency of URs decreased with increasing age. This supports a physiological regression of URs with age. Stopak et al. attributed this upsurge to increased awareness among community pediatricians and improvements in US that made visualisation of urachal remnants easier [1222]. Clinical studies and paediatric autopsy studies in the past have shown a much lower incidence. Rubin found an incidence of 1 in 7,610 cases of patent urachus and 1 in 5,000 cases of urachal cysts [1223]. Nix et al. noted three anomalies out of 1,168,760 hospital admissions, and Blichert-Toft et al. reported five UR cases out of 40,000 patients [1224, 1225]. The incidence rate in males is a little higher than in females [1226, 1227]. The range of the various URs reported in the literature is 10% to 48% for patent urachus, 31% to 43% for urachal cyst, 18% to 43% for urachal sinus and 3% to 4% for urachal diverticulum [1228, 1229]. 3.19.1.3 Symptoms A patent urachus causes continuous or intermittent urine leakage from the umbilicus causing umbilical granulation and erythema in infants [1228]. A urachal cyst is usually diagnosed (1) incidentally, or (2) when it becomes infected causing abdominal pain and discharge of pus from the umbilicus or recurrent UTIs when it drains into the bladder. The most common symptom is umbilical granulation, discharge and erythema in infants and abdominal pain in older children [1228]. Other symptoms of infected urachal anomalies can vary from high fever, abdominal pain, urinary tract infections, LUTS and/or an abdominal mass [1229-1233]. A urachal diverticulum is often asymptomatic and is usually found incidentally during investigations for other problems. An alternating sinus can empty either into the bladder or the umbilicus and this characteristic is responsible for various presentations [1234]. Infection has been reported as the most common complication in urachal anomalies [1235]. Severe infection may develop into peritonitis and sepsis. Cultures from umbilical discharge usually show Staphylococcus, Streptococcus and E. Coli [1236]. • Other congenital anomalies: Ashley found a simultaneous anomaly in 17 of 46 children, of which VUR was the most common anomaly (6 patients) [1237]. Other investigators reported associated anomalies in cases of persistent URs including meatal stenosis, hypospadias, umbilical and inguinal hernias, cryptorchidism, anal atresia, omphalocele, ureteropelvic obstruction and most frequently, VUR [1227, 1238-1240]. 3.19.1.4 Diagnosis In the majority of cases with complaints of a UR, a careful history and physical examination will confirm the suspicion of a UR. In many patients this can be confirmed by US studies [1221]. An MRI or CT scan may be necessary in a minority of children [1232]. Because of the association with other congenital abnormalities, other studies such as a VCUG or cystoscopy may be undertaken as well. In general, the VCUG is only undertaken when the child also presents with UTI or when the US shows signs of upper tract abnormalities. For the diagnosis per se it is not necessary [1241]; however, a VCUG may be useful for defining the type of urachal anomaly and evaluating a population that may be at higher risk for VUR. 3.19.1.5 Treatment If a UR is symptomatic, the standard approach has been surgical removal. In most cases it should be done as an elective procedure, following appropriate treatment of active inflammation, and infection is possible.

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Pre-operative IV-dosage of antibiotic like Cefazolin is generally sufficient. A Pfannenstiel, periumbilical or infraumbilical midline incision can all be used for the open surgical approach [1231, 1242]. Even in symptomatic infants a more conservative approach is possible as well, especially in children less than six months old. Observation and treatment with antibiotics if necessary and radiographic monitoring are a safe approach [1228, 1243, 1244]. Dethlefs et al. reported a 90% successful outcome [1230], while Naiditch et al. reported that 44 of 78 symptomatic patients resolved under observation [1233]. More recently the laparoscopic approach has been advocated, and shown to be safe [1244-1246]. Surgery is not without risk. The rate of complications following surgical removal varies from 0 to 20%: usually wound infections [1222, 1230-1233, 1242]. Considering the probable additional risk of anaesthesia in very young children any surgical procedure needs to be assessed carefully [1247, 1248]. 3.19.1.6 Pathology of removed remnants Removed specimens may show inflammation or a cystic structure [1230]. Patients presenting without symptoms are as likely to have epithelial elements in the UR as those presenting with symptoms [1232]. 3.19.1.7 Urachal cancer Urachal anomalies are thought to be associated with an increased risk of bladder adenocarcinoma in adults, and urachal adenocarcinoma has an estimated incidence of 0.18 per 100,000 individuals yearly [1249]. These cases account for 0.1 to 0.3% of all bladder malignancies and 20 to 39% of bladder adenocarcinomas [1250]. Urachal adenocarcinoma (UrC) is very rare, especially when one considers that up to 62% of children under 16 years of age may have a UR [1221, 1251]. A study by Copp et al. found no association between the presence of UR symptoms and the presence or absence of epithelial tissue in pathology specimens, leading them to conclude that UR symptoms have poor predictive value for malignancy potential in these remnants [1227]. Gleason et al. found that 5,721 URs would need to be excised to prevent a single case of urachal adenocarcinoma out of the nearly 65,000 patients reviewed [1249]. Assuming that epithelium is required in the development of urachal adenocarcinoma, the extrapolated Number Needed to Treat (NNT) would be more than 8,000, as nearly 30% of urachal anomalies are void of an epithelial component. Less than 5% of urachal cancers have a non-epithelial origin such as sarcoma [1252]. The presenting symptoms in adults are different from those in children: in a study of 130 adult patients, Ashley et al. found that 49% presented with haematuria and 27% with pain. In 51% a urachal carcinoma was diagnosed: adenocarcinoma, with 58% high grade cancer. In addition, 20% had metastases at diagnosis, the overall 5-year cancer specific survival rate in the UrC cohort was 49% [1253]. Stasis of urine and crystallisation promotors such as mucus or desquamated epithelium in the UR are most likely the cause for malignant degeneration as well as stone formation in the adult patient. At present no long-term follow-up on untreated UR in children is available and there is no evidence that urachal anomalies in children increase the likelihood of future malignancy [1228, 1254]. 3.19.1.8 Conclusion Urachal remnants appear to be more common than previously reported. During the first 6-12 months of life spontaneous resolution is common. Excision of symptomatic urachal anomalies is an effective and safe means of treatment, with minimal morbidity. However, most patients with simple and asymptomatic lesions do not appear to benefit from excision, as the risk of malignancy later in life is vanishingly remote. Early intervention (< 6 months of age) should be reserved for patients with persistent documented urine draining from the urachus or a documented abscess. Incidental (US) UR management remains a challenge and should be done with patient and family involvement to make the most informed decision. While surgical intervention has minimal risk and morbidity, it is performed unnecessarily in a large proportion of asymptomatic patients due to the unnecessary removal of non-epithelial containing urachal anomalies and the inability to predict which anomalies will undergo malignant transformation [1255]. 3.19.1.9

Recommendation for management of urachal remnants

Recommendations Urachal remnants with no epithelial tissue carry little risk of malignant transformation. Asymptomatic and non-specific atretic urachal remnants can safely be managed nonoperatively. Urachal remnants (URs) incidentally identified during diagnostic imaging for non-specific symptoms should also be observed non-operatively since they tend to resolve spontaneously. A small urachal remnant, especially at birth, may be viewed as physiological. Urachal remnants in patients younger than 6 months are likely to resolve with non-operative management.

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Follow-up is necessary only when symptomatic for 6 to 12 months. Surgical excision of urachal remnants solely as a preventive measure against later malignancy appears to have minimal support in the literature. Only symptomatic URs should be safely removed by open or laparoscopic approach. A VCUG is only recommended when presenting with febrile UTIs.

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Papillary tumours of the bladder in children and adolescents (Papillary urothelial neoplasm of low malignant potential or transitional cell carcinoma) 3.19.2.1 Incidence Papillary tumours of the bladder in children and adolescents are extremely rare and are different from papillary tumours in adults. A “grape-like” papillary tumour in young children will be more likely a rhabdomyosarcoma of the bladder, which are not the focus of this guideline. A papillary tumour in older children or adolescents will be more likely be a papillary urothelial neoplasm of low malignant potential (PUNLMP) [1256]. Children with risk factors, such as previous bladder surgery and immunosuppressive medication can also develop a nephrogenic adenoma of the bladder, also presenting as a papillary tumour of the bladder. 3.19.2

3.19.2.2 Differences and similarities of papillary tumours of the bladder in children and adults Gender The overall the risk of a papillary tumour in the bladder in paediatric and young adult patients is approximately double in males compared to females [1257]. 3.19.2.3 Risk factors The majority of these patients have no identifiable risk factors. 3.19.2.4 Presentation The most common symptom at presentation is haematuria; other less common symptoms include abdominal pain, storage LUTS including frequency, dysuria and at times obstructive symptoms [1257]. 3.19.2.5 Investigations and treatment Ultrasound of the genitourinary tract is the first investigation of choice. It is an excellent screening tool and can often accurately diagnose the nature and location of lesion. In children and adolescents, a bladder US of the full bladder is more sensitive compared with adults due to reduced abdominal fat and thinner muscle layer [1258]. In the event of a need to differentiate the renal or bladder origin of the haematuria, a red blood cell morphology will reveal isomorphic blood cells, differentiating a bladder origin. Urine cytology can be performed, however it has very limited value likely due to the low-grade nature of these tumours in children. Cystoscopy should be reserved if a bladder tumour is suspected on imaging for simultaneous diagnosis and treatment, transurethral resection of the tumour. In children, cystoscopy requires general anaesthesia [1259]. 3.19.2.6 Histology All the lesions in the children and adolescent age-group are identified as papillary and over 85% are solitary [1258]. Papillary bladder tumours in patients younger than twenty years of age have low-grade non-invasive disease (WHO classification) [1260]. These findings let pathologists conclude that in children and adolescents, a papillary bladder tumour can be classified as Papillary Urothelial Neoplasm of Low Malignant Potential (PUNLMP). PUNLMP has minimal or no cytological atypia and it differs from low grade transitional cell carcinoma (TCC) which has cytologic atypia, hyperchromatic nuclei and scattered mitosis [1261]. 3.19.2.7 Additional treatment Mitomycin C and Bacillus Calmette-Guerin have both been used in children but there is no evidence of their efficacy due to the rarity of TCC, and especially of high grade TCC [1257]. Hence, as per current evidence, there is no place for instillations in children. 3.19.2.6 Prognosis, recurrence and surveillance The prognosis of papillary tumours of the bladder in children is overall good. The recurrence rate in children and adolescents varies from 8 to 15% [1256-1258]. Mean time to recurrence can vary from 11 to 29 months depending on the study, with recurrences occurring up to 90 months from diagnosis; though 64% occur in the first year [1257]. In certain cases, recurrences can be fairly aggressive [1258]. Strategies are based on the guidelines and protocols of papillary tumours of the bladder in adults. It is advised to follow-up children and adolescents with a history of a PUNLMP initially with a short interval of three to six months in the first year, and thereafter at least yearly with urinanalysis for haematuria and an US of the full bladder. In the event of sudden gross haematuria, the evaluation must be performed immediately. If

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the tumour was completely resected at primary surgery, standard follow-up cystoscopy is not necessary and may be reserved for children or adolescents with a high recurrence risk or suspected recurrence on bladder US [1258]. The exact duration of follow-up is unknown but this Panel recommends follow-up for at least five years. Inflammatory myofibroblastic tumours of the bladder (IMTB) are rare with nearly 200 cases reported in the literature [1262, 1263]. Around 25% occur in children with a median age at diagnosis of 7.5 years and a median tumour size of 5.5 cm. Boys and girls are equally affected [1264]. Usually these tumours are benign, with only very few reported malignant cases [1265]. Treatment is mostly surgical with transurethral resection, but local resection, or partial cystectomy maybe needed in selected cases [1264, 1266]. Additionally, a conservative approach is reported [1267]. Histological examination is required to exclude other malignant tumours such as a rhabdomyosarcoma. In children, no recurrence has been reported so far. However due to the malignant potential and few recurrences in adults, follow-up as for papillary bladder tumours is recommended. Summary of evidence Majority of paediatric patients have no identifiable risk factors for bladder tumours. There is no evidence on intravesical therapy for bladder tumours in children and adolescents. Prognosis of papillary tumours of the bladder in children is good overall. Inflammatory myofibroblastic bladder tumours are usually benign. Recommendations Ultrasound is the first investigation of choice for the diagnosis of paediatric bladder tumours. Cystoscopy should be reserved if a bladder tumour is suspected on imaging for diagnosis and treatment. After histological confirmation, inflammatory myofibroblastic bladder tumours should be resected locally. Follow-up should be every 3-6 months in the first year, and thereafter at least annually with urinanalysis and an ultrasound for at least 5 years.

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3.19.3 Penile rare conditions Paediatric lesions of the penis are uncommon but an important part of the paediatric urological practice. The commonest of these lesions are cystic penile lesions followed by vascular malformations and neurogenic lesions [1268]. Soft tissue tumours of the male external genitalia are uncommon, but have been described in the paediatric age group and can be malignant [1269]. 3.19.3.1 Cystic lesions • Epidermal inclusion cysts are the commonest genital cystic lesion and can occur anywhere on the body in both men and women; in the penis it occurs most commonly over the penile shaft varying from 0.1 to 1 cm in diameter. Their epithelium is lined and filled with keratin. It is a painless swelling and can present in the age group with a history of circumcision. Treatment by total surgical excision is mainly indicated for cosmetic or symptomatic (e.g. infection) reasons and should be performed without rupturing the cyst to avoid recurrence [1270]. •

Mucoid cyst of the penis is synonymous with parameatal cyst or genitoperineal cyst of median raphe; they are midline developmental cysts arising from ectopic urethral mucosa filled with mucoid material. They present since birth but are usually detected during adolescence or later. They are usually asymptomatic developing over penile ventral surface around glans and require surgical removal for either cosmetic, functional or symptomatic reasons [1271].

•

Median raphe cysts arise from incomplete closure of genital fold during embryogenesis; they are commonly diagnosed in the first decade of life but can present later as they tend to be asymptomatic [1272]. They are either unilocular or multilocular fluid containing cysts, with a mean size of 0.8 cm but cysts larger than 2 cm have also been reported [1273]. Cysts are centred in dermis, with no connection to urethra or epidermis. Histopathologically, there are 4 types: urethral (urothelium-like epithelium, account for 55% cases), epidermoid, glandular and mixed. They can be treated conservatively and can resolve spontaneously or persist. Cyst aspiration is associated with high risk of recurrence and surgical excision is the treatment of choice. Though most penile cysts are asymptomatic, they may get infected resulting in pain and tenderness. They can also present with ulceration, rupture and urinary obstruction if they are

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close to the urethral meatus. This along with cosmetic issues means that most caregivers and patients opt for surgical excision. •

Smegmal cysts or smegmal pearls can be a differential for the cysts above; they are a benign collection of smegma in the sub-preputial space in uncircumcised boys with anticipated spontaneous resolution [1274].

•

Dermoid cyst are congenital, asymptomatic, firm, solitary, subcutaneous cystic lesions occurring commonly in the region of the corona involving the foreskin. Histopathologically they contain sweat and sebaceous glands with elements of hair and squamous epithelium. Pilosebaceous cysts have been described on the glans; they are benign and usually diagnosed after excision.

3.19.3.2 Vascular malformations A broad classification of penile vascular lesions into haemangiomas and vascular malformations was proposed by Ramos in 1999 [1275]. Haemangiomas develop rapidly at birth and involute slowly; they also include pyogenic granulomas which are benign outgrowths of cutaneous capillary vessels formed usually from chronic irritation [1268]. The growth cycle of infantile haemangiomas is divided into early and late proliferative stages, followed by a slow involution phase, completing growth by nine months of age [1276]. Propranolol is currently first line treatment for infantile haemangiomas, the exact mechanism of action is unknown but can include inhibition of angiogenesis, vasoconstriction among others. The dose is in the range of 1.5-2.5 mg/kg, which needs to be continued for 12 to 18 months and then tapered through active or passive weaning to reduce risk of rebound growth [1276]. Other factors leading to rebound growth after propranolol treatment include deep haemangiomas, which occur in about 38% patients despite propranolol therapy, requiring local therapy such as topical timolol, pulsed dye laser or intralesional steroids. After twelve months, the median improvement with treatment is reported as 81% (range 70-90%) based on VAS scores of serial patient photographs. Vascular malformations are congenital lesions of capillary, lymphatic and venous (or slow-flow) or arterial/ arteriovenous (fast-flow) origin that enlarge slowly as the patient grows. These include glomus tumours, which are primarily congenital arteriovenous shunts that develop from thermo-regulatory glomus bodies (fastflow vascular malformations). Glomus tumours of the penis can arise on the glans penis, corpora of the penis and as periurethral masses, sometimes accompanied by glomus tumours of fingers and feet [1277]. These are usually asymptomatic at presentation or may have symptoms such as priapism, palpitation and perineal pain. Glomus tumours are benign despite exhibiting high grade nuclear polymorphism. Vascular malformations are usually benign and treated either with laser, sclerotherapy or surgical excision. However, glomus tumours specifically need surgical treatment and follow-up due to the risk of recurrence from incomplete excision [1278]. 3.19.3.3 Neurogenic lesions Penile neurofibroma is an extremely rare lesion arising from perineural and Schwann cells, and occurs usually with evidence of systemic neurofibromatosis or von Recklinghausen syndrome [1279]. They are treated successfully with complete excision [1268]. Rare cases of malignant schwanomas on the penis presumably secondary to malignant transformation of benign neurofibromas have been reported in boys with a strong family history of neurofibromatosis. This type of malignant degeneration of neurofibromatosis occurs in reportedly 5-16% children [1279]. Hence, these patients require long-term follow-up due to risk of recurrence, new tumour formation and malignant transformation. 3.19.3.4 Soft tissue tumours of penis Mesenchymal tumours are rare in the external genitalia and they require excision in order to differentiate between benign and malignant neoplasms. Histopathological characterisation is essential to ensure malignant tumours receive radical treatment with adjuvant therapy or close follow-up [1269]. Presentation is usually of a painless penile mass, that is non-tender and rubbery on examination. Ultrasound maybe useful in characterising the lesion but is not diagnostic; it can exclude urethral invasion if it is close to urethra [1269]. Once an excision biopsy is performed, if aggressive malignant components are found, a further wider resection may be needed. Fibrosarcoma is a rare non-rhabdomyosarcoma soft tissue tumour that arises from fibrous tissue. The infantile form of fibrosarcoma is rare and those occurring on the penis are even rarer in the paediatric age-group. Surgical intervention has a favourable prognosis in the paediatric age group with long-term survival of 90% in sporadic cases [1280]. Myofibroma is a benign congenital lesion that occurs either as a solitary lesion or as a part of myofibromatosis with multiple soft tissue tumours. Excision is necessary for histological diagnosis [1269].

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Primary penile teratomas are extremely rare subtype of congenital germ cell tumours, and they tend to be asymptomatic and are subdermal on US with no blood flow on Doppler [1281]. They need aggressive treatment with surgical resection due to their unpredictable behavior and unresponsiveness to chemotherapy. Mature teratomas are benign but immature teratoma or even mixed teratomas with immature components can turn malignant and have the potential to metastasise and recur. 3.19.3.5 Penile Lymphedema Lymphedema in adults is usually secondary to malignancy or infectious disease affecting lymphatic drainage. In the paediatric age group, however, lymphedema is usually primary and generally very rare, affecting 1.2 per 100.000 persons under the age of 20 years [1282]. Of these, only a very small fraction relates to the genital region. Regardless of underlying aetiology, inefficient lymphatic drainage leads to accumulation of subcutaneous lymph which causes tissue swelling and inflammation. This in turn stimulates adipose deposition and fibrosis further exacerbating enlargement. With time the edematous tissue becomes vulnerable to infection, chronic cutaneous changes and disfigurement [1283]. Additionally, when occurring in the genital region urological complications may ensue; such as phimosis, haematuria, bleeding, bladder outlet obstruction, pain, dysuria, lymphorrhea and severe psychological distress due to resultant deformity [1284, 1285]. In the largest cohort of male genital oedema in the paediatric age group, 92% of cases were primary; of these only 25% had a discernable familial or syndromic association such as Noonan syndrome, lymphedemadistichiasis or Milroy disease [1284]. Secondary genital lymphedema in children has been reported after inguinal surgery, and non-caseating granulomatous lymphangitis as seen with metastatic Crohn’s disease [1284-1286]. Average age of onset was reported to be 4.5 ± 6.3 years with 61% presenting in infancy, 13% in childhood and the remaining 26% in adolescence. Edema is usually penoscrotal in 72%, isolated scrotal in 24% and very rarely confined exclusively to the penis in 4%. Moreover, concomitant lower limb edema is the rule in two thirds of cases [1284]. There is no general consensus on diagnostic work-up of these patients. History and physical examination (including family history) is usually sufficient. However lymphoscintigraphy can be used as a confirmatory test, more so for limb than genital edema where results can be difficult to interpret [1284]. Ultrasonography is nonspecific, but has been advocated by some to exclude secondary lymphedema by examining the patency of iliac and caval vessels [1287]. Magnetic resonance imaging is useful to exclude other differential diagnoses such as other venous or lymphatic anomalies [1284]. Conservative treatment is the accepted first-line treatment. The mainstay is compression therapy to maintain and prevent further swelling. This can be achieved by compression stockings and undergarments. Additionally, close observation and protection of the skin to prevent excoriations and infection is essential [1284, 1287]. Compression therapy is however, less effective on genital oedema than it is on limb edema, especially in growing children. When conservative management fails, and especially in symptomatic cases, or in patients with functional impairment, surgical debulking may be necessary. This can either take the form of circumcision in cases where the foreskin is affected or excision of affected skin and subcutaneous tissues with restructuring and contouring for optimal cosmetic outcome. Complete skin excision and grafting may also be required [1284-1287]. Surgical management can be challenging and needs to be restricted to patients with significant symptoms. Complications include recurrences, continuous lymphatic leakage, haematoma, infection and poor cosmetic outcome [1282, 1287, 1288]. Summary of evidence Cystic penile lesions are the commonest paediatric penile lesions followed by vascular malformations and neurogenic lesions. Neurofibroma patients require long-term follow-up due to risk of recurrence, new tumour formation and malignant transformation. Mesenchymal tumours are rare and require excision in order to differentiate between benign and malignant neoplasms.

Recommendations Treatment of penile cystic lesions is by total surgical excision, it is mainly indicated for cosmetic or symptomatic (e.g. infection) reasons. Propranolol is currently the first-line treatment for infantile haemangiomas. Conservative management is the first-line treatment for penile lymphedema. In symptomatic cases or in patients with functional impairment, surgical intervention may become necessary for penile lymphedema. 102

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3.20

Paediatric urological trauma

Trauma is the leading cause of morbidity and mortality in children and is responsible for more childhood deaths than the total of all other causes [1289]. In about 3% of children seen at paediatric hospital trauma centres, there is significant involvement of the genitourinary tract [1290]. This is caused by either blunt injuries from falls, car accidents, sports injuries, physical assault, sexual abuse, or penetrating injuries, usually due to falls onto sharp objects or from gunshot or knife wounds. 3.20.1 Paediatric renal trauma 3.20.1.1 Epidemiology, aetiology and pathophysiology In blunt abdominal trauma, the kidney is the most commonly affected organ, accounting for about 10% of all blunt abdominal injuries [1289]. Children are more likely than adults to sustain renal injuries after blunt trauma because of their anatomy. Compared to an adult kidney, a child’s kidney is larger in relation to the rest of the body and often retains foetal lobulations, so that blunt trauma is more likely to lead to a local parenchymal disruption. The paediatric kidney is also less well protected than the adult kidney. Children have less peri-renal fat, much weaker abdominal muscles, and a less ossified and therefore much more elastic and compressible thoracic cage [1291]. Blunt renal trauma is usually a result of sudden deceleration of the child’s body, particularly due to sport accidents, falls, and contact with blunt objects. Deceleration or crush injuries result in contusion, laceration or avulsion of the less well-protected paediatric renal parenchyma. 3.20.1.2 Classification systems Renal injuries are classified according to the kidney injury scale of the American Association for the Surgery of Trauma (Table 7) [1292]. Table 7: R  enal injury classified according to the kidney injury scale of the American Association for the Surgery of Trauma [1292] Grade I II III IV V

Type of injury Contusion Haematoma Haematoma Laceration Laceration Laceration Vascular Laceration Vascular

Description Non-visible or visible haematuria Normal urological studies Non-expanding subcapsular haematoma Laceration of the cortex of < 1.0 cm Laceration > 1.0 cm without rupture of collecting system Through the cortex, medulla and collecting system Vascular injury Completely shattered kidney Avulsion of the renal hilum

3.20.1.3 Diagnostic evaluation In a child who has sustained blunt abdominal trauma, renal involvement can often be predicted from the history, physical examination and laboratory evaluation. Renal involvement may be associated with abdominal or flank tenderness, lower rib fractures, fractures or vertebral pedicles, trunk contusions and abrasions, and haematuria. 3.20.1.3.1 Haematuria Haematuria may be a reliable finding. In severe renal injuries, 65% suffer visible haematuria and 33% nonvisible, while only 2% have no haematuria at all [1293]. The radiographic evaluation of children with suspected renal trauma remains controversial. Some centres rely on the presence of haematuria to diagnose renal trauma, with a threshold for renal involvement of 50 RBCs/HPF. Although this may be a reliable threshold for significant non-visible haematuria in trauma, there have been many reports of significant renal injuries that manifest with little or even no blood in the urine [1294]. It is therefore compulsory to consider all the clinical aspects involved, including the history, physical examination, consciousness of the child, overall clinical status and laboratory findings to decide on the diagnostic algorithm and whether or not a child needs further imaging studies. 3.20.1.3.2 Blood pressure It is important to consider that children, unlike adults, are able to maintain their blood pressure, even in the presence of hypovolaemia, due to compliance of the vascular tree and mechanisms for cardiac compensation [1295]. As blood pressure is an unreliable predictor of renal involvement in children, some centres recommend imaging of the urinary tract in children with any degree of haematuria following significant abdominal trauma.

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3.20.1.3.3 Choice of imaging method Nowadays, CT is the best imaging method for renal involvement in children. Computed tomography scanning is the cornerstone of modern staging of blunt renal injuries especially when it comes to grading the severity of renal trauma. Computed tomography scanning is quite rapid and usually performed with the injection of contrast media. To detect extravasation, a second series of images is necessary since the initial series usually finishes 60 seconds after injection of the contrast material and may therefore fail to detect urinary extravasation. In acute trauma, US may be used as a screening tool and for reliably following the course of renal injury. However, US is of limited value in the initial and acute evaluation of trauma. The standard intravenous pyelogram (IVP) is a good alternative imaging method if a CT scan is not available. It is superior to US but not as good as CT scanning for diagnostic purposes. 3.20.1.4 Disease management The modern management of trauma is multidisciplinary, requiring paediatricians, emergency physicians, surgeons, urologists, and other specialties as required. Non-surgical conservative management with bed rest, fluids and monitoring has become the standard approach for treating blunt renal trauma. Even in high-grade renal injuries, a conservative approach is effective and recommended for stable children. However, this approach requires close clinical observation, serial imaging, and frequent re-assessment of the patient’s overall condition. Therefore, a good initial trauma CT with delayed images to check for urinary extravasation is recommended since this may prevent repeat ionising scans. In stable patients with grade 2 or higher lesions a close follow up with US 48 to 72 hours after the initial scan is sufficient and should be considered before repeating a CT scan [1296]. A systematic review supports application of conservative management protocols also to high-grade blunt paediatric renal trauma. At this time, emergent operative intervention only for haemodynamic instability is recommended. Minimally invasive interventions including angio-embolisation, stenting, and percutaneous drainage should be used when indicated [1297]. Absolute indications for surgery include persistent bleeding into an expanding or unconfined haematoma. Relative indications for surgery are massive urinary extravasation and extensive non-viable renal tissue [1298]. A recently published meta-analysis concluded with the following recommendations: (1) In paediatric patients with blunt renal trauma of all grades, non-operative management vs. operative management in haemodynamically stable patients is strongly recommended. (2) In haemodynamically stable paediatric patients with high-grade (AAST grade III-V) renal injuries, angio-embolisation vs. surgical intervention for ongoing or delayed bleeding is strongly recommended; and, (3) In paediatric patients with renal trauma, routine blood pressure checks to diagnose hypertension is recommended in the long-term follow-up [1299]. However, long-term data on the risk of developing hypertension is lacking. 3.20.1.5

Recommendations for the diagnosis and management of paediatric renal trauma

Recommendations Use imaging in all children who have sustained a blunt or penetrating trauma with any level of haematuria, especially when the history reveals a deceleration trauma, direct flank trauma or a fall from a height. Use rapid spiral computed tomography with delayed images scanning for diagnostic and staging purposes. Manage most injured kidneys conservatively. Offer surgical intervention in case of haemodynamic instability and a Grade V renal injury.

Strength rating Strong

Strong Strong Strong

3.20.2 Paediatric ureteral trauma Injuries to the ureter are rare. The ureter is well protected; the upper part is protected by its close approximation to the vertebral column and paraspinal muscles and the lower part by its route through the bony pelvis. In addition, the ureter is a small target, and both flexible and mobile. This also means that ureteral injuries are caused more often by penetrating trauma than blunt trauma [1300]. Since the ureter is the sole conduit for urinary transport between the kidney and the bladder, any ureteral injury can threaten the function of the ipsilateral kidney. 3.20.2.1 Diagnostic evaluation Since there are no classical clinical symptoms suggestive of ureteral trauma, it is important to carry out a careful diagnostic work-up using different imaging modalities. Unfortunately, initial imaging studies, such as IVP and routine CT scans, are unreliable. A study of eleven disruptions of the ureteropelvic junction found that 72% had a normal or non-diagnostic IVP on initial studies [1300]. Diagnostic accuracy of CT scanning can be

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improved by performing a delayed CT scan up to ten minutes after injection of the contrast material [1301]. The most sensitive diagnostic test is a retrograde pyelogram. Quite a few patients present several days after the injury, when the urinoma produces flank and abdominal pain, nausea and fever. Due to symptoms being often vague, it is important to remain suspicious of a potential undiagnosed urinary injury following significant blunt abdominal trauma in a child. 3.20.2.2 Management Immediate repair during abdominal exploration is rare. Minimally invasive procedures are the method of choice, especially since many ureteral injuries are diagnosed late after the traumatic event. Percutaneous or nephrostomy tube drainage of urinomas can be successful, as well as internal stenting of ureteral injuries [1302]. If endoscopic management is not possible, primary repair of partial lacerations should be followed by internal stenting. The management of complete lacerations, avulsions or crush injuries depends on the amount of ureter lost and its location. If there is an adequate healthy length of ureter, a primary ureteroureterostomy can be performed. If primary re-anastomosis is not achievable, distal ureteral injuries can be managed using a psoas bladder hitch, Boari flap or even nephropexy. Proximal injuries can be managed using transureteroureterostomy, auto-transplantation or ureteral replacement with bowel or appendix [1303]. 3.20.2.3

Recommendations for the diagnosis and management of paediatric ureteral trauma

Recommendations Diagnose suspected ureteral injuries by retrograde pyelogram. Manage ureteral injuries endoscopically, using internal stenting or drainage of an urinoma, either percutaneously or via a nephrostomy tube.

Strength rating Strong Weak

3.20.3 Paediatric bladder injuries The paediatric bladder is less protected than the adult bladder, and is therefore more susceptible to injuries than the adult bladder, especially when it is full, due to: • Its higher position in the abdomen and its exposure above the bony pelvis. • The fact that the abdominal wall provides less muscular protection. • The fact that there is less pelvic and abdominal fat surrounding the bladder to cushion it in trauma. Blunt trauma is the most common cause of significant bladder injury. In adults, bladder injury is often associated with pelvic fractures. This is less common in children because the paediatric bladder sits above the pelvic ring. In a large prospective study, only 57% of children with pelvic fractures also had a bladder injury compared to 89% of adults [1304]. 3.20.3.1 Diagnostic evaluation The characteristic signs of bladder injury are suprapubic pain and tenderness, an inability to urinate, and visible haematuria (95% of injuries). Patients with a pelvic fracture and visible haematuria present with a bladder rupture in up to 45% of cases [1305]. The diagnosis of bladder rupture can be difficult in some cases. The bladder should be imaged both when fully distended and after drainage using standard radiography or a CT scan. The best results can be achieved by retrograde filling of the bladder using a catheter. Despite advances in CT imaging, the bladder must still be filled to capacity to accurately diagnose a possible bladder injury [1306]. Blunt injuries to the bladder are categorised as: • contusions with damage to the bladder mucosa or muscle, without loss of bladder wall continuity or extravasation; • ruptures, which are either intraperitoneal or extraperitoneal. Intraperitoneal bladder ruptures are more common in children because of the bladder’s exposed position and the acute increase in pressure during trauma. These cause the bladder to burst at its weakest point, i.e. the dome. Extraperitoneal lesions occur in the lower half of the bladder and are almost always associated with pelvic fractures. A cystogram will show extravasation into the perivesical soft tissue in a typical flame pattern and the contrast material is confined to the pelvis. 3.20.3.2 Management Contusions usually present with varying degrees of haematuria and are treated with catheter drainage alone.

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3.20.3.2.1 Intraperitoneal injuries The accepted management of intraperitoneal bladder ruptures is open surgical exploration and primary repair. Post-operative drainage with a suprapubic tube is mandatory. Recent data suggest that transurethral drainage may be as effective, with fewer complications, resulting in shorter periods of diversion [1307]. Usually, after about seven to ten days, a repeat cystogram is performed to ensure healing is taking place properly. 3.20.3.2.2 Extraperitoneal injuries Non-operative management with catheter drainage for seven to ten days alone is the method of choice for extraperitoneal bladder rupture. However, if there are bone fragments within the bladder, these must be removed and the bladder must then be repaired and drained, according to the principles for treating intraperitoneal ruptures [1308]. 3.20.3.3

Recommendations for the diagnosis and management of paediatric bladder injuries

Recommendations Use retrograde cystography to diagnose suspected bladder injuries. Ensure that the bladder has been filled to its full capacity and an additional film is taken after drainage. Manage extra-peritoneal bladder ruptures conservatively with a transurethral catheter left in place for seven to ten days. Do not delay treatment of intra-peritoneal bladder ruptures by surgical exploration and repair as well as post-operative drainage for seven to ten days.

Strength rating Strong Strong Strong Strong

3.20.4 Paediatric urethral injuries Except for the penile part of the urethra, the paediatric urethra is quite well protected. In addition, its shape and elasticity mean the urethra is seldom injured by trauma. However, a urethral injury should be suspected in any patient with a pelvic fracture or significant trauma to the perineum until confirmed otherwise by a diagnostic work-up. 3.20.4.1 Diagnostic evaluation Patients with suspected urethral trauma and pelvic fractures usually present with a history of severe trauma, often involving other organ systems. Signs of urethral injury are blood at the meatus, visible haematuria, and pain during voiding or an inability to void. There may also be perineal swelling and haematoma involving the scrotum. A rectal examination to determine the position and fixation of the prostate is important in any male with a suspected urethral injury. The prostate, as well as the bladder, may be displaced up out of the pelvis, especially in membranous urethral trauma. Radiographic evaluation of the urethra requires a retrograde urethrogram. It is important to expose the entire urethral length, including the bladder neck. If a catheter has already been placed by someone else and there is suspected urethral trauma, the catheter should be left in place and should not be removed. Instead, a small infant feeding tube can be placed into the distal urethra along the catheter to allow the injection of contrast material for a diagnostic scan [1309]. 3.20.4.2 Disease management Since many of these patients are unstable, the urologist’s initial responsibility is to provide a method of draining and monitoring urine output. A transurethral catheter should only be inserted if there is a history of voiding after the traumatic event, and if a rectal and pelvic examination, as described above, has not suggested a urethral rupture. If the catheter does not pass easily, an immediate retrograde urethrogram should be performed. A suprapubic tube may be placed in the emergency department percutaneously, or even in the operating room, if the patient has to undergo immediate exploration because of other life-threatening injuries. There are often no associated injuries with a bulbous urethral or straddle injury and management is therefore usually straightforward. In these cases, a transurethral catheter is the best option for preventing urethral bleeding and/or painful voiding [1310]. The initial management of posterior urethral injuries remains controversial, mainly regarding the long-term results with primary realignment compared to simple suprapubic drainage with later reconstruction. The main goals in the surgical repair of posterior urethral injuries are: • Providing a stricture-free urethra. • Avoiding the complications of urinary incontinence and impotence.

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Suprapubic drainage and late urethral reconstruction was first attempted because immediate surgical repair had a poor outcome, with significant bleeding and high rates of incontinence (21%) and impotence in up to 56% of cases [1311]. In adults, a study of the success rates of delayed repair reported re-structure rates of 11-30%, continence rates of 90-95% and impotence rates of 62-68% [1312]. However, in children, there is significantly less experience with delayed repair. The largest paediatric series of delayed repair in 68 boys reported a success rate of 90% [1313]. Another study reported strictures and impotence in 67% of boys, although all the boys were continent [1129]. A recently published follow-up study on 15 patients who underwent delayed urethroplasty for blunt urethral trauma during childhood reported high long-term success rates with a low rate of long-term urinary and sexual dysfunction in adulthood [1314]. An alternative to providing initial suprapubic drainage and delayed repair is primary realignment of the urethra via a catheter. The catheter is usually put in place during open cystostomy by passing it from either the bladder neck or meatus and through the injured segment. In a series of fourteen children undergoing this procedure, this resulted in a stricture rate of 29% and incontinence in 7% of patients [1315]. 3.20.4.3

Recommendations for the diagnosis and management of paediatric trauma

Recommendations Assess the urethra by retrograde urethrogram in case of suspected urethral trauma. Perform a rectal examination to determine the position of the prostate. Manage bulbous urethral injuries conservatively with a transurethral catheter. Manage posterior urethral disruption by either: • primary reconstruction; • primary drainage with a suprapubic catheter alone and delayed repair; • primary re-alignment with a transurethral catheter.

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Strength rating Strong Strong Strong Weak

Peri-operative fluid management

3.21.1 Epidemiology, aetiology and pathophysiology Children have a different total body fluid distribution, renal physiology and electrolyte requirements, as well as weaker cardiovascular compensation mechanisms, compared to adults [1316]. During development, children have a high metabolic rate and lower fat and nutrient stores which means they are more susceptible to metabolic disturbances caused by surgical stress [1317]. The metabolic response to anaesthesia and surgery in infants and children is related to the severity of the operation [1318]. 3.21.2 Disease management 3.21.2.1 Pre-operative fasting Pre-operative fasting has been advocated for elective surgery to avoid the complications associated with pulmonary aspiration during induction of anaesthesia. New regimens include a 30-60 minute limitation for clear liquids [1319, 1320] without increased risk of pulmonary aspiration [1321]. Several studies have shown that fasting times in clinical practice often exceed the guidelines with average fasting times of 6-10 hours [1320-1322]. Compared to adults, children have a higher metabolic rate and low glycogen stores and impaired gluconeogenesis, which makes hypoglycaemia an important issue to consider, especially in children < 36 months old [1320]. Therefore, it is important to prevent too long fasting times. Clear-liquid carbohydrate drinks have been proposed to reduce these fasting times [1323]. Table 8 provides the current six, four and one hour guidelines for pre-operative fasting for elective surgery [1320, 1322]. Table 8: Pre-operative fasting times for elective surgery Ingested material Clear liquids Breast milk Light meal

Minimum fasting period (hours) 1 4 6

3.21.2.2 Maintenance therapy and intra-operative fluid therapy Generally, the anaesthetist is responsible for intra-operative management and the surgeon is responsible for post-operative instructions. The goal of intra-operative fluid management is to sustain homeostasis by providing the appropriate amount of parenteral fluid; this maintains adequate intravascular volume, cardiac

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output and oxygen delivery to tissues at a time when normal physiological functions have been altered by surgical stress and anaesthetic agents. In recent years new strategies for maintenance and replacement fluid management have been developed and this has changed intra-operative fluid management significantly. The main goal of intra-operative fluid management is to maintain a normal extracellular fluid volume (EFV). During the intra-operative period fluid deficits may be induced by blood loss or pre-operative fasting. These fluid deficits can be replaced by balanced isotonic electrolyte solutions to restore a normal EFV. It is recommended that maintenance intravenuous (IV) fluids should consist of balanced isotonic solutions with appropriate potassium chloride and dextrose in order to decrease the risk of hyponatraemia development [1324]. No increased risk for hypernatraemia, fluid overload with aedema and hypertension, and hyperchloremic acidosis was found, which was always feared for isotonic solutions [1324]. When children are clinically unstable due to third-space losses, these losses should be replaced with crystalloids (normal saline or Ringer’s lactate). Third-space losses may vary from 1 mL/kg/h for a minor surgical procedure to 15-20 mL/kg/h for major abdominal procedures, or even up to 50 mL/kg/h for surgery of necrotising enterocolitis in premature infants. When this fluid management is insufficient replacement management with colloids (albumin, gelatine and hydroxyethyl starch (HES) should be adopted, using a restrictive approach [1325]. Clinical guidelines have been proposed by Sümpelmann et al. [1325] regarding intra-operative fluid management (Table 9). Table 9: Intra-operative fluid management

Background infusion Fluid therapy Volume therapy Transfusion

Solution for infusion Balanced isotonic solution + 1-2% glucose Balanced isotonic solution Albumin, Gelatine, hydroxyethyl starch Red blood cells, fresh frozen plasma, platelets

Initial/repeated dose 10 mL/kg/h X 10-20 mL/kg X 5-10 mL/kg X 10 mL/kg

3.21.2.3 Post-operative feeding and fluid management It is not obligatory to check serum chemistry after uncomplicated surgery in children with normal pre-operative renal and hepatic function. However, if oral intake has been postponed for > 24 hours (e.g. as in intestinal surgery), there is an increased risk of electrolyte abnormalities, requiring further assessment and subsequent management, particularly with potassium. Post-operative findings, such as decreased bowel movements and ileus, may be signs of hypokalaemia. Children who undergo interventions to relieve any kind of obstructive diseases deserve particular attention, especially due to the risk of polyuria as a result of post-obstructive diuresis [1326]. In children who develop polyuria, it is important to monitor fluid intake and urine output, as well as renal function and serum electrolytes. If necessary, clinicians should not hesitate in consulting with a paediatric nephrologist. In children who have undergone non-abdominal surgery, studies have suggested that gastric motility returns to normal one hour after emergence from anaesthesia [1327]. Early post-operative intake of fluid in children who have undergone minor or non-abdominal urological surgery is associated with reduced post-operative vomiting and lower opioid use [1328] and is therefore encouraged. In abdominal surgery the enhanced recovery after surgery (ERAS) protocol has been implemented in the paediatric population following its success in adults [1323, 1329]. The ERAS protocol is a multimodal approach to prevent the post-operative effects of the surgical stress response. This protocol includes pre- and intraoperative element such as minimal pre-operative fasting and careful intra-operative fluid management, and also focuses on post-operative care. The post-operative ERAS protocol suggests starting clear fluid intake on the evening of surgery and a normal diet the day after surgery and thereby early discontinuation of IV fluids. Further focus is on early mobilisation, preventing epidurals and omitting or early removal of external tubes [1323, 1329]. The implementation of an ERAS protocol has resulted in shorter length of hospital stays, faster bowel recovery and opioid-free post-operative need [1323, 1329, 1330]. When implementing ERAS in children with neurological abnormalities special attention should be given to bowel management with pre-operative treatment of constipation and early post-operative continuation of routine bowel management.

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3.21.3

Summary of evidence and recommendations for the management of peri-operative fluid management

Summary of evidence Children are not simply smaller physiological versions of adults. They have their own unique metabolic features, which must be considered during surgery. During the intra-operative period balanced isotonic electrolyte solutions can be used to maintain a normal extracellular fluid volume. Following abdominal surgery ERAS protocols can be used to reduce recovery times and complications.

Recommendations Ensure shorter pre-operative fasting periods for elective surgeries (up to one hour for clear liquids). Use ERAS protocols for abdominal surgery in children with normal bowel movement. Use isotonic solutions in hospitalised children because they are at high risk of developing hyponatraemia. Assess the baseline and daily levels of serum electrolytes, glucose, urea and/or creatinine in every child who receives intravenous fluids, especially in intestinal surgery (e.g. ileal augmentation), regardless of the type of solution chosen since there is an increased risk of electrolyte abnormalities in children undergoing such surgery. Start early oral fluid intake in all patients scheduled for minor surgical procedures.

3.22

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Strength rating Strong Strong Strong Strong

Strong

Post-operative pain management: general information

3.22.1 Epidemiology, aetiology and pathophysiology The provision of adequate pain control requires proper pain evaluation, accurate choice of drug and route of administration, and consideration of age, physical condition and type of surgery and anaesthesia [1331]. Traditional medical beliefs that neonates are incapable of experiencing pain have now been abandoned following recent and better understanding of how the pain system matures in humans, better pain assessment methods and a knowledge of the clinical consequences of pain in neonates [1332, 1333]. Many studies have indicated that deficient or insufficient analgesia may be the cause of future behavioural and somatic sequelae [1334, 1335]. Our current understanding of pain management in children depends fully on the belief that all children, irrespective of age, require adequate pain treatment. 3.22.2 Diagnostic evaluation Assessment of pain is the first step in pain management. Several pain assessment tools have been validated according to the child’s age, cultural background, mental status, communication skills and physiological reactions [1336]. Depending on the child’s age, the 0-10 Numeric Rating Scale, Faces Revised Pain Scale or Colour Analog Scale, for example, can be used [1337]. One of the most important topics in paediatric pain management is informing and involving the child and caregivers during this process. Patient-familycontrolledanalgesia is the preferred pain management in the hospital and at home if provided with the correct information [1337, 1338]. 3.22.3 Disease management 3.22.3.1 Drugs and route of administration Pre-emptive analgesia is an important concept that aims to induce the suppression of pain before neural hypersensitisation occurs [1339]. Regional anaesthesia are given intra-operatively which can include a regional nerve block, caudal blocks or local wound infiltration and has proven to reduce the need for post-operative analgesia [1340]. The WHO’s ‘pain ladder’ is a useful tool for the pain management strategy [1341]. A three level strategy seems practical for clinical use. Post-operative management should be based on sufficient intraoperative pre-emptive analgesia with regional or caudal blockade followed by balanced analgesia. Paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) are the drugs of choice at the first level. As they become insufficient to prevent pain, weak and strong opioids are added to oral drugs to achieve balanced analgesia. Every institute must build their own strategy for post-operative analgesia. A proposed strategy for postoperative analgesia may be as follows: 1. Intra-operative regional or caudal block. 2. Paracetamol + NSAID. 3. Paracetamol + NSAID + weak opioid (e.g. tramadol or codeine). 4. Paracetamol + NSAID + strong opioid (e.g. morphine, fentanyl, oxycodone or pethidine).

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The use of opioids in children has long held a standard role in the post-operative management of pain. Increased recognition of the adverse effects of opioids and prolonged opioid dependency demand a balanced intra-operative administration of opioids [1337, 1342]. Intra-operative adequate dosage of paracetamol and NSAIDs results in a decrease in opioid requirement in children [1343, 1344]. Furthermore, opioid awareness among physicians could reduce opioid use. When prescribing lower opioid dosage, this did not increase pain scores in urological outpatient surgeries [1345]. Caution is necessary to take account of renal function when using NSAIDs. Paediatric dependent dosages for most common used pain medication can be found in this publication [1346]. 3.22.3.2 Circumcision Circumcision requires anaesthesia and proper pain management [1347]. Potential analgesic interventions during circumcision include the use of a dorsal penile nerve block (DPNB) or ring block, topical anaesthetics (e.g. lidocaine-prilocaine cream, or 4% liposomal lidocaine cream), and sucrose preferably in combination [1340, 1346]. Caudal blockade methods have similar efficacy compared to DPNB. However, caregivers should be informed about the more frequent incidence of post-operative motor weakness and micturition problems [1348]. Ultrasound guidance can be used [1346]. 3.22.3.2.1 Penile, inguinal and scrotal surgery Caudal blocks and peripheral nerve blocks (DPNB and pudendal) are commonly used methods for analgesia following surgery for hypospadias. Several agents with different doses, concentrations and administration techniques have been used and shown to be adequate. Overall post-operative pain scores were lower with pudendal nerve blocks. No increase in post-operative complications was seen with these types of blocks [1340, 1349, 1350]. Severe bladder spasms caused by the presence of the bladder catheter may sometimes cause more problems than pain and is managed with antimuscarinic medications. For inguinoscrotal surgery, various regional anaesthesia methods have been investigated, such as transversus abdominis plane block, ilioinguinal/iliohypogastric nerve blocks and caudal blocks. All have been shown to have adequate postoperative analgesic properties. Additional local anaesthetics such as clonidine or dexmedetomidine may improve results [1340]. 3.22.3.3 Bladder and kidney surgery Continuous local infusion reduces the need for post-operative opioids [1351-1353], as well as systemic (intravenous) application of analgesics [1354], has been shown to be effective. Ketorolac is an effective agent that is underused. It decreases the frequency and severity of bladder spasms and the length of post-operative hospital stay and costs [1355, 1356]. Open kidney surgery is particularly painful because all three muscle layers are cut during conventional loin incision. A dorsal lumbotomy incision may be a good alternative because of the shorter post-operative hospital stay and earlier return to oral intake and unrestricted daily activity [1357]. Caudal and paravertebral blocks continuous epidural analgesia, as well as rectus sheath and transversus abdominis plane blocks have decreased post-operative morphine requirement after abdominal and renal surgery [1358-1360]. For laparoscopic approaches, intra-peritoneal spraying of local anaesthetic before incision of the perirenal fascia may be beneficial [1361]. 3.22.4

Summary of evidence and recommendations for the management of post-operative pain

Summary of evidence Adequate paracetamol and NSAIDs use reduces opioid need post-operatively. Pain may cause behavioural and somatic sequelae. Every institute must develop their own well-structured strategy for post-operative analgesia.

Recommendations Prevent/treat pain in children of all ages. Evaluate pain using age-compatible assessment tools. Inform patients and caregivers accurately. Use pre-emptive and balanced analgesia in order to decrease the side effects of opioids.

3.23

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Basic principles of laparoscopic surgery in children

3.23.1 Epidemiology, aetiology and pathophysiology The use of laparoscopy and robot-assisted laparoscopic surgery is rapidly increasing and has gained widespread acceptance for many urological surgeries in children. Diagnostic laparoscopy for undescended

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testis, nephrectomy, heminephrectomy, varicocelectomy, pyeloplasty and ureteral reimplantation are some of the indications which are commonly being performed. This expanding scope related to technological advancements allows surgeons to perform more complex procedures in a minimally invasive fashion even in infants and younger children. Generally, well established benefits of minimally invasive surgery are decreased pain, shorter convalescence and better cosmetics compared to traditional open surgery [807]. Additional advantages of robotic surgery over conventional laparoscopy include ergonomics, 3D vision, better manoeuvrability, decreased tremor and easy learning curve. Limitations to be considered are increased operative time, smaller working space at young age, cost and experience of the surgeon and anaesthesiologist. While the success and complication rates are comparable for nephrectomy and pyeloplasty (see chapter 3.13.3.2) advantages of laparoscopy and robotic surgery for ureteral reimplantation have not been proven and this can only be recommended for experienced centres (see chapter 3.14.3.2.3). As worldwide experience increases, there is an accumulating awareness about the physiological consequences related to intra- and retroperitoneal carbon dioxide (CO2) insufflation in children. In contrast to traditional open surgery pneumoperitoneum may have physiological responses which require close monitoring during surgery and should be taken seriously. 3.23.2 Technical considerations and physiological consequences 3.23.2.1 Pre-operative evaluation Laparoscopy in children requires specific anaesthetic precautions. Physiological effects of CO2 pneumoperitoneum, positioning of the patient and in potentially increased operative time need to be considered by the anaesthesiology team. Therefore, a detailed medical examination and risk assessment is mandatory pre-operatively. Especially cardiac and pulmonary system should be assessed since increased intra-abdominal pressure may lead to decreased ventricular preload [1362]. 3.23.2.2 Abdominal insufflation Abdominal insufflation is the main principle of laparoscopic surgery to create working space for the surgeon. Carbon dioxide is the most commonly used insufflant in laparoscopic centres throughout the world. Other alternatives reported are nitrous oxide, helium, argon and air. However, CO2 is considered to be the best available gas as it is colourless, cheap, has high solubility in the vascular system [1363] and is excreted by the pulmonary system making it the safest option. Smaller children and infants absorb more CO2 than older children [1364], suggesting the need for more attention both during and early after laparoscopic surgery for these children. Most complications of laparoscopy are attributable to gaining access to the abdominal cavity. One study reporting complications of > 5,400 paediatric laparoscopic surgeries showed that there was an overall complication rate of 5.3% of which 4.2% were related to problematic insufflation (subcutaneous emphysema, gas embolism, injury to the organs and vascular structures, mis-insufflation etc.) [1365]. There are two main and well-established techniques for initial access to the abdomen or retroperitoneum: open technique (Hasson) and Veress needle. Studies comparing these two different access techniques in paediatric laparoscopic urological procedures showed similar complication rates [1366]. The vast majority of the complications were minor and related to lack of surgical experience. Particularly in infants and smaller children, the open access technique is recommended by the Panel to reduce the chance of complications. Elasticity of the abdominal wall is age-related and is higher in infants and small children compared to older children [1367]. Pneumoperitoneal pressure (PnP in mmHg) is one of the critical points that needs to be carefully considered by laparoscopic surgeons. A recent RCT compared two different pneumoperitoneal pressure groups (6-8 mmHg vs. 9-10 mmHg) in infants less than 10 kg [1368]. It demonstrated that higher pressures were associated with more pronounced respiratory and haemodynamic changes as well as increased post-operative pain scores and prolonged time to resume feeding. 3.23.2.3 Pulmonary effects After intra-abdominal insufflation the diaphragm is pushed upwards due to increased abdominal pressure. This leads to decreased total pulmonary compliance. Combined with CO2 absorption this may lead to hypercarbia and acidosis, particularly in case of prolonged operative time or low pulmonary reserve such as in infants. Trendelenburg position may also aggravate the situation in operations in the pelvic region, such as anti-reflux or bladder neck surgeries. Several studies revealed increased end tidal CO2 (ET CO2) related to CO2 absorption [1364, 1369, 1370]. One study showed a 33% increase in ET CO2 in the majority of neonatal laparoscopic and

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thoracoscopic procedures [1187]. Shorter operative time and lower intra-abdominal pressures decrease the risk of increased ET CO2. Hypoxemia is rarely seen, even in neonates and can easily be adjusted by increasing minute ventilation. These findings highlight the importance of close monitoring of the children. 3.23.2.4 Cardiovascular effects Intra-abdominal pressure, CO2 absorption and positioning may also affect the cardiovascular system. It has been shown in adults that after initiation of pneumoperitoneum, cardiac output and stroke volume decrease while mean arterial pressure, central venous pressure and systemic vascular resistance increase [1371]. Similar outcomes have been reported during paediatric laparoscopy with some nuances. Cardiac output was 30% decreased while blood pressure remained stable during laparoscopic orchidopexy with PnP of 10 mmHg in children between aged 6-30 months [1372]. When PnP was lowered from 12 mmHg to 6 mmHg, cardiac index and other vascular parameters normalised [1373]. Using high intra-abdominal pressures in infants with congenital cardiac abnormalities may result in re-opening of cardiac shunts such as the foramen ovale and ductus arteriosus [1374]. Although cardiovascular effects of using high PnP are clinically measurable, they may not have a significant clinical impact on healthy children. However, it is clear that using lower pressures is safer especially in smaller children. 3.23.2.5 Effects on renal function Although clinical studies in children are lacking, pneumoperitoneum may also have adverse effects on renal blood flow [1375]. High intra-abdominal pressures and reverse Trendelenburg position may cause decreased glomerular filtration rate and decreased urine output. One study has shown that 88% of infants and 14% of children more than one year old develop anuria within 45 minutes after initiation of PnP with 8 mmHg [1376]. However, urine output recovers with temporary polyuria after the operation. Although the clinical relevance of decreased urine output seems insignificant, it is important to monitor the fluid and electrolyte balance of the children during and after laparoscopic surgery. 3.23.2.6 Effects on neurological system Another effect of pneumoperitoneum is increased intracranial pressure (ICP) which normalises after desufflation of the abdomen [1377]. Trendelenburg position, high PnP and hypoventilation are additional risk factors for increased ICP. Laparoscopy is therefore contraindicated in patients with intracranial space occupying lesions [1378]. Children with ventriculo-peritoneal shunts require precautions with regards to shunt drainage, however laparoscopy is not contraindicated [1379]. 3.23.3

Summary of evidence and recommendations for laparoscopy in children

Summary of evidence Laparoscopy and robotic-assisted laparoscopic surgery can safely be performed in children. The general benefits of laparoscopy are decreased pain, shorter convalescence and better cosmetics compared to traditional open surgery. Limitations to be considered are increased operative time, smaller working space with young age, cost, surgeon and anaesthesiologist experience. Pneumoperitoneum may have physiological effects which require close monitoring during surgery and should be taken seriously. Recommendations Use lower intra-abdominal pressure (6-8 mmHg) during laparoscopic surgery in infants and smaller children. Use open access for laparoscopy in infants and smaller children. Monitor for laparoscopy-related cardiac, pulmonary and diuretic responses.

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Bosakova, A., et al. Diffusion-weighted magnetic resonance imaging is more sensitive than dimercaptosuccinic acid scintigraphy in detecting parenchymal lesions in children with acute pyelonephritis: A prospective study. J Pediatr Surg, 2018. 14: 269. https://pubmed.ncbi.nlm.nih.gov/29588142 Michaud, J.E., et al. Cost and radiation exposure in the workup of febrile pediatric urinary tract infections. J Surg Res, 2016. 203: 313. https://pubmed.ncbi.nlm.nih.gov/27363638 Siomou, E., et al. Implications of 99mTc-DMSA scintigraphy performed during urinary tract infection in neonates. Pediatrics, 2009. 124: 881. https://pubmed.ncbi.nlm.nih.gov/19661052 Shaikh, N., et al. Dimercaptosuccinic acid scan or ultrasound in screening for vesicoureteral reflux among children with urinary tract infections. Cochrane Database Syst Rev, 2016. 2016: CD010657. https://pubmed.ncbi.nlm.nih.gov/27378557 Mazzi, S., et al. Timing of voiding cystourethrography after febrile urinary tract infection in children: A systematic review. Arch Dis Child, 2019. 105: 264. https://pubmed.ncbi.nlm.nih.gov/31466991 Spencer, J.D., et al. The accuracy and health risks of a voiding cystourethrogram after a febrile urinary tract infection. J Pediatr Urol, 2012. 8: 72. https://pubmed.ncbi.nlm.nih.gov/21126919 Ntoulia, A., et al. Contrast-enhanced voiding urosonography (ceVUS) with the intravesical administration of the ultrasound contrast agent Optison for vesicoureteral reflux detection in children: a prospective clinical trial. Pediatr Radiol, 2018. 48: 216. https://pubmed.ncbi.nlm.nih.gov/29181582 Lee, L.C., et al. The role of voiding cystourethrography in the investigation of children with urinary tract infections. Can Urol Assoc J, 2016. 10: 210. https://pubmed.ncbi.nlm.nih.gov/27713802 Pauchard, J.-Y., et al. Avoidance of voiding cystourethrography in infants younger than 3 months with Escherichia coli urinary tract infection and normal renal ultrasound. Arch Dis Child, 2017. 102: 804. https://pubmed.ncbi.nlm.nih.gov/28408468 Shaikh, N., et al. Identification of children and adolescents at risk for renal scarring after a first urinary tract infection: a meta-analysis with individual patient data. JAMA Pediatr, 2014. 168: 893. https://pubmed.ncbi.nlm.nih.gov/25089634 Rianthavorn, P., et al. Probabilities of Dilating Vesicoureteral Reflux in Children with First Time Simple Febrile Urinary Tract Infection, and Normal Renal and Bladder Ultrasound. J Urol, 2016. 196: 1541. https://pubmed.ncbi.nlm.nih.gov/27181502 Bahat, H., et al. Predictors of grade 3-5 vesicoureteral reflux in infants T1G2: invasive lymph node staging by either bilateral modified inguinal lymphadenectomy or dynamic sentinel node biopsy. Radical inguinal lymphadenectomy.

Strength rating

Neoadjuvant chemotherapy followed by radical inguinal lymphade-nectomy in responders. Ipsilateral pelvic lymphadenectomy if two or more inguinal nodes are involved on one side (pN2) or if extracapsular nodal metastasis (pN3) reported In pN2/pN3 patients after radical lymphadenectomy. Not recommended for nodal disease except as a palliative option.

Weak

Strong Strong

Strong

Strong

Strong Strong

6.3.6 Guidelines for chemotherapy Recommendations Offer patients with pN2-3 tumours adjuvant chemotherapy after radical lymphadenectomy (three to four cycles of cisplatin, a taxane and 5-fluorouracil or ifosfamide). Offer palliative chemotherapy to patients with systemic disease.

Strength rating Strong

Weak

A systematic review (SR) was performed by the Panel on ‘Risks and benefits of adjuvant radiotherapy after inguinal lymphadenectomy in node-positive penile cancer’ [2]. Even though not fully published, the review findings support the information presented in Section 6.2.2.3 Adjuvant treatment. This review was performed using standard Cochrane SR methodology: http://www.cochranelibrary. com/about/about-cochrane-systematic-reviews.html

2.

METHODS

2.1

Data identification

For the 2018 Penile Cancer Guidelines, new and relevant evidence has been identified, collated and appraised through a structured assessment of the literature. A broad and comprehensive literature search, covering all sections of the Penile Cancer Guidelines, was performed. Databases searched included Medline, EMBASE and the Cochrane Libraries, covering the period between November 1st 2013 and September 20th 2016. All articles relating to penile cancer (n = 838) in the relevant literature databases were reviewed resulting in the inclusion of 29 new publication in this print.

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5

Fully revised Guidelines were produced using the updated research base, together with several national and international guidelines on penile cancer (National Comprehensive Cancer Network [3], French Association of Urology [4] and the European Society of Medical Oncology [5]). For the 2018 edition of the EAU Guidelines the Guidelines Office have transitioned to a modified GRADE methodology across all 20 guidelines [6, 7]. For each recommendation within the guidelines there is an accompanying online strength rating form which addresses a number of key elements namely: 1. the overall quality of the evidence which exists for the recommendation, references used in this text are graded according to a classification system modified from the Oxford Centre for Evidence-Based Medicine Levels of Evidence [8]; 2. the magnitude of the effect (individual or combined effects); 3. the certainty of the results (precision, consistency, heterogeneity and other statistical or study related factors); 4. the balance between desirable and undesirable outcomes; 5. the impact of patient values and preferences on the intervention; 6. the certainty of those patient values and preferences. These key elements are the basis which panels use to define the strength rating of each recommendation which is represented by the words ‘strong’ or ‘weak’ [9]. The strength of each recommendation is determined by the balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including certainty of estimates), and nature and variability of patient values and preferences. The strength rating forms will be available online. Additional information can be found in the general Methodology section of this print, and online at the EAU website: http://www.uroweb.org/guideline/. A list of associations endorsing the EAU Guidelines can also be viewed online at the above address.

3.

EPIDEMIOLOGY, AETIOLOGY AND PATHOLOGY

3.1

Definition of penile cancer

Penile carcinoma is usually a SCC and there are several recognised subtypes of penile SCC with different clinical features and natural history (see Table 1). Penile SCC usually arises from the epithelium of the inner prepuce or the glans. Table 1: Histological subtypes of penile carcinomas, their frequency and outcome Subtype

Frequency Prognosis (% of cases) Common squamous cell carcinoma 48-65 Depends on location, stage and grade (SCC) Basaloid carcinoma 4-10 Poor prognosis, frequently early inguinal nodal metastasis [10] Warty carcinoma 7-10 Good prognosis, metastasis rare Verrucous carcinoma 3-8 Good prognosis, no metastasis Papillary carcinoma 5-15 Good prognosis, metastasis rare Sarcomatoid carcinoma 1-3 Very poor prognosis, early vascular metastasis Mixed carcinoma 9-10 Heterogeneous group Pseudohyperplastic carcinoma T1G2: invasive lymph node staging by either bilateral modified inguinal lymphadenectomy or dynamic sentinel node biopsy. Radical inguinal lymphadenectomy.

Strength rating

Neoadjuvant chemotherapy followed by radical inguinal lymphadenectomy in responders.

Weak

Strong Strong

Strong

PENILE CANCER - MARCH 2018

Pelvic lymph nodes

Adjuvant chemotherapy Radiotherapy

6.3

Ipsilateral pelvic lymphadenectomy if two or more inguinal nodes are involved on one side (pN2) or if extracapsular nodal metastasis (pN3) reported. In pN2/pN3 patients after radical lymphadenectomy. Not recommended for nodal disease except as a palliative option.

Strong

Strong Strong

Chemotherapy

6.3.1 Adjuvant chemotherapy in node-positive patients after radical inguinal lymphadenectomy Multimodal treatment can improve patient outcome. Adjuvant chemotherapy after radical lymphadenectomy in node-positive patients has been reported in a few small and heterogeneous series [158-160]. Comparing different small-scale clinical studies is fraught with difficulty. The value of adjuvant chemotherapy after radical inguinal lymphadenectomy in node-positive penile cancer was first demonstrated by a study which reported long-term (DFS) of 84% in 25 consecutive patients treated with twelve adjuvant weekly courses of vincristine, bleomycin, and methotrexate (VBM) during 19791990 and compared this to a historical control group of 38 consecutive node-positive patients with radical lymphadenectomy (with- or without adjuvant inguinal radiotherapy) who had achieved a DFS rate of only 39% [161]. The same group also published results of an adjuvant chemotherapy regimen with three courses of cisplatin and 5-FU with lower toxicity and even better results compared to VBM [176] (LE: 2b). The same group has published results of adjuvant chemotherapy with cisplatin, 5-FU plus paclitaxel or docetaxel (TPF), with three to four cycles after resection of pN2-3 disease [177]. Of 19 patients, 52.6% were disease-free after a median follow up of 42 months and tolerability was good. Results of adjuvant treatment with paclitaxel and cisplatin also improved outcome [178]. Therefore, the use of adjuvant chemotherapy is recommended, in particular when the administration of the triple combination chemotherapy is feasible and there is curative intent (LE: 2b). There are no data concerning adjuvant chemotherapy in stage pN1 patients. Adjuvant chemotherapy in pN1 disease is, therefore, recommended only in clinical trials. 6.3.2 Neoadjuvant chemotherapy in patients with fixed or relapsed inguinal nodes Bulky inguinal lymph node enlargement (cN3) indicates extensive lymphatic metastatic disease. Primary lymph node surgery is not generally recommended since complete surgical resection is unlikely and only a few patients will benefit from surgery alone. Limited data is available on neoadjuvant chemotherapy before inguinal lymph node surgery. However, it allows for early treatment of systemic disease and down-sizing of the inguinal lymph node metastases. In responders, complete surgical treatment is possible with a good clinical response. Results of neoadjuvant chemotherapy for bulky inguinal lymph node metastases were modest in retrospective studies including five to twenty patients treated with bleomycin-vincristine-methotrexate (BVM) or bleomycin-methotrexate-cisplatin (BMP) regimens [162, 163, 179], as well as in the confirmatory BMP trial of the Southwest Oncology Group [180]. However, treatment-related toxicity was unacceptable due to bleomycinrelated mortality. Cisplatin/5-FU (PF) chemotherapy achieved a response rate of 25-50% with more acceptable toxicity [181, 182]. Over a period of 30 years, five different neoadjuvant chemotherapy regimens were used in twenty patients [87], with long-term survival in 37% of responders who underwent radical lymph node surgery after neoadjuvant chemotherapy. In the EORTC cancer study 30992, 26 patients with locally advanced or metastatic disease received irinotecan and cisplatin chemotherapy. Although the study did not meet its primary endpoint (response rate), there were three cases of pathologically complete remissions [183]. A phase II trial evaluated treatment with four cycles of neoadjuvant paclitaxel, cisplatin, and ifosfamide (TIP). An objective response was reported in 15/30 patients, including three pathologically complete remissions (pCRs). The estimated median time to progression (TTP) was 8.1 months and the median OS was 17.1 months [164] (LE: 2a). Hypothetical similarities between penile SCC and head and neck SCC led to the evaluation, in penile cancer, of chemotherapy regimens with an efficacy in head and neck SCC, including taxanes. The combination of cisplatin and 5-FU plus a taxane has been used in neoadjuvant and adjuvant settings [177]. An overall objective response rate of 44% was reported in 28 patients treated neoadjuvantly, including 14% pCR (LE: 2b). Similarly, a phase II trial with TPF using docetaxel instead of paclitaxel reported an objective response of 38.5% in 29 locally advanced or metastatic patients, although the study did not meet its primary endpoint. However, there was significant toxicity [184] (LE: 2a). Further evidence of the benefit of neoadjuvant chemotherapy was published recently [165].

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21

Overall, these results support the recommendation that neoadjuvant chemotherapy using a cisplatin- and taxane-based triple combination should be used in patients with fixed, unresectable, nodal disease (LE: 2a). There are hardly any data concerning the potential benefit of radiochemotherapy together with lymph node surgery in penile cancer. It should therefore only be used in controlled clinical trials [185]. 6.3.3 Palliative chemotherapy in advanced and relapsed disease A recent retrospective study of 140 patients with advanced penile SCC reported that visceral metastases and an > 1 ECOG-performance status were independent prognostic factors, and that cisplatin-based regimens had better outcomes than non-cisplatin-based regimens after adjusting for prognostic factors [186] (LE: 3). Before taxanes were introduced, chemotherapy data in penile cancer were limited by small numbers, patient heterogeneity and retrospective design (except for the EORTC trial [183]). Initial response rates ranged from 25% to 100%, with very few sustained responses and very few long-term survivors. The introduction of taxanes into penile cancer chemotherapy has enhanced the activity and efficacy of the regimens used [87, 162-164, 178-184, 187]. There are virtually no data on second-line chemotherapy in penile cancer. One report using second-line paclitaxel monotherapy reported a response rate of < 30% and no patient survived [188] (LE: 2a). Anecdotally, a benefit of second-line cisplatin with gemcitabine has been observed [189] (LE: 4). 6.3.4 Intra-arterial chemotherapy Intra-arterial chemotherapy which refers to intra-aortic application has been trialled in locally advanced cases, especially of cisplatin and gemcitabine in small case series [190-193]. Apart from a limited clinical response, the outcome was not significantly improved. 6.3.5 Targeted therapy Targeted drugs have been used as second-line treatment and they could be considered as single-agent treatment in refractory cases. Anti-epidermal growth factor receptor (EGFR) targeted monotherapy has been trialled [194], as EGFR is expressed in penile SCC [190, 191] and there are assumed similarities with head and neck SCC [190, 191]. There have been other studies, particularly with the anti-EGFR monoclonal antibodies panitumumab and cetuximab, without long-term response, however [195]. Some activity of tyrosine kinase inhibitors has been reported as well [193]. Further clinical studies are needed (LE: 4). 6.3.6

Guidelines for chemotherapy

Recommendations Offer patients with pN2-3 tumours adjuvant chemotherapy after radical lymphadenectomy (three to four cycles of cisplatin, a taxane and 5-fluorouracil or ifosfamide). Offer patients with non-resectable or recurrent lymph node metastases neoadjuvant chemotherapy (four cycles of a cisplatin- and taxane-based regimen) followed by radical surgery. Offer palliative chemotherapy to patients with systemic disease.

7.

FOLLOW-UP

7.1

Rationale for follow-up

Strength rating Strong Weak

Weak

Early detection of recurrence increases the likelihood of curative treatment since local recurrence does not significantly reduce long-term survival if successfully treated [87, 196]. In contrast, disease that has spread to the inguinal lymph nodes greatly reduces the rate of long-term DSS. Follow-up is also important in the detection and management of treatment-related complications. Local or regional nodal recurrences usually occur within two years of primary treatment [87]. After five years, all recurrences were either local or new primary lesions [87]. This supports an intensive follow-up regimen during the first two years, with a less intensive follow up later for a total of at least five years. Followup after five years may be omitted in motivated patients who will undertake regular self-examination reliably [87].

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PENILE CANCER - MARCH 2018

7.1.1 When and how to follow-up After local treatment with negative inguinal nodes, follow-up should include physical examination of the penis and groins for local and/or regional recurrence. Additional imaging has no proven benefit. Follow-up also depends on the primary treatment modality. Histology from the glans should be obtained to confirm diseasefree status following laser ablation or topical chemotherapy. After potentially curative treatment for inguinal nodal metastases, CT or MRI imaging for the detection of systemic disease should be performed at three-monthly intervals for the first two years. Although rare, late local recurrence may occur, with life-threatening metastases becoming very unusual after five years. Therefore, regular follow up can be stopped after five years, provided the patient understands the need to report any local changes immediately [197]. In patients unlikely to self-examine, longterm follow up may be necessary. 7.1.2 Recurrence of the primary tumour Local recurrence is more likely with all types of local organ-sparing treatment but does not influence the rate of cancer-specific survival in contrast to regional lymph node recurrence [87, 196]. Local recurrence occurred during the first two years in up to 27% of patients treated with penis-preserving modalities [98]. After partial penectomy, the risk of local recurrence is about 4-5% [87, 98, 196]. Local recurrence is easily detected by physical examination, by the patient himself or his physician. Patient education is an essential part of follow-up and the patient should be urged to visit a specialist if any changes are seen. 7.1.3 Regional recurrence Most regional recurrences occur during the first two years after treatment, irrespective of whether surveillance or invasive nodal staging were used. Although unlikely, regional recurrence can occur later than two years after treatment. It is therefore advisable to continue follow up in these patients [197]. The highest rate of regional recurrence (9%) occurs in patients managed by surveillance, while the lowest is in patients who have undergone invasive nodal staging by modified inguinal lymphadenectomy or DSNB and whose lymph nodes were negative (2.3%). The use of US and fine needle aspiration cytology (FNAC) in suspicious cases has improved the early detection rate of regional recurrence [76, 198, 199]. There are no data to support the routine use of CT or MRI for the follow-up of inguinal nodes. Patients who have had surgery for lymph node metastases without adjuvant treatment have an increased risk of regional recurrence of 19% [87]. Regional recurrence requires timely treatment by radical inguinal lymphadenectomy and adjuvant chemotherapy (see Section 6). 7.1.4

Guidelines for follow-up in penile cancer Interval of follow-up

Examinations and investigations

Years Years one to two three to five Recommendations for follow-up of the primary tumour Penile-preserving Three Six months Regular physician treatment months or self-examination. Repeat biopsy after topical or laser treatment for penile intraepithelial neoplasia. Amputation Three One year Regular physician or ­ months self-examination. Recommendations for follow-up of the inguinal lymph nodes Surveillance Three Six months Regular physician or months self-examination. pN0 at initial Three One year Regular physician treatment months or self-examination. Ultrasound with fineneedle aspiration biopsy optional.

PENILE CANCER - MARCH 2018

Minimum duration Strength rating of follow-up

Five years

Strong

Five years

Strong

Five years

Strong

Five years

Strong

23

pN+ at initial treatment

7.2

Three months

Five years Six months Regular physician or self-examination. Ultrasound with fineneedle aspiration cytology optional, computed tomography/ magnetic resonance imaging optional.

Strong

Quality of life

7.2.1 Consequences after penile cancer treatment In patients with long-term survival after penile cancer treatment, sexual dysfunction, voiding problems and cosmetic penile appearance may adversely affect the patient’s QoL [200]. However, there is very little data on sexual function and QoL after treatment for penile cancer. In particular, there is heterogeneity of the psychometric tools used to assess QoL outcomes and further research is needed to develop disease-specific patient reported outcome measures for penile cancer. Comparative studies There are only two comparative studies in the literature reporting on the health-related quality of life (HRQoL) outcomes following surgery for localised penile cancer. One study compared wide local excision with glansectomy [201]. Among 41 patients there was reduction in post-operative International Index of Erectile Function (IIEF) and the authors concluded that local excision led to better sexual outcomes than glansectomy. In another study of 147 patients, the IIEF-15, the SF36 Health Survey and the Impact of Cancer questionnaire were used [202]. Compared to an age-matched population sample, men after partial penectomy reported significantly more problems with orgasm, cosmesis, life interference and urinary function than those who had undergone penile-sparing surgery (83% vs. 43%, p < 0.0001). Interestingly, there were no differences in erectile function, sexual desire, intercourse satisfaction or overall sexual satisfaction. 7.2.2 Sexual activity and quality of life after laser treatment A retrospective interview-based Swedish study after laser treatment for penile PeIN [104] in 58 out of 67 surviving patients with a mean age of 63 years, of whom 46 participated, reported a marked decrease in some sexual practices, such as manual stimulation, caressing and fellatio, but a general satisfaction rate with life overall and sexuality which was similar to that of the general Swedish population. A large study on CO2 laser treatment of penile cancer in 224 patients reported no problems with erectile or sexual function following treatment [91]. In another study [107], no sexual dysfunction occurred in nineteen patients treated. 7.2.3 Sexual activity after glans resurfacing In one study with ten patients [111], 7/10 completed questionnaires (IIEF-5 and a non-validated 9-item questionnaire) at six months. The median IIEF-5 score was 24 (no erectile dysfunction). All patients who were sexually active before treatment were active after three to five months, 7/7 stated that the sensation at the tip of their penis was either no different or better after surgery, and 5/7 patients felt that their sex life had improved. Overall patient satisfaction with glans resurfacing was high. 7.2.4 Sexual activity after glansectomy Two studies reported sexual function after glansectomy [112, 113]. In one (n = 68) with unclear methodology [113], 79% did not report any decline in spontaneous erection, rigidity or penetrative capacity after surgery, and 75% reported recovery of orgasm. In the other study [114], all twelve patients had returned to ‘normal’ sexual activity one month after surgery. 7.2.5 Sexual function after partial penectomy Sexual function after partial penectomy was reported by three studies [203-205]. In one with 18 patients with a mean age of 52 years, the IIEF scores were significantly worse for all domains of sexual function after surgery [203] and 55.6% of patients had erectile function that allowed sexual intercourse. In patients who did not resume sexual activity, 50% were ashamed of their small penis and missing glans, while another third blamed surgical complications. Of those who had resumed sexual intercourse, 66.7% reported the same frequency and level of sexual activity as before surgery, while 72.2% continued to have ejaculation and orgasm every time with sexual activity. Overall, only 33.3% maintained their pre-operative frequency of sexual intercourse and were satisfied with their sex life.

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PENILE CANCER - MARCH 2018

In another study, an ‘Overall Sexual Functioning Questionnaire’ was used in 14 patients with a median time of 11.5 months after surgery (range 6-72) [204]. Prior to surgery, all patients had had normal erectile function and intercourse at least once a month. In 9/14 patients, sexual function was ‘normal’ or ‘slightly decreased’, while 3/14 had had no sexual intercourse since surgery. Alei et al. reported an improvement in erectile function over time [205]. In a report of 25 patients after partial penectomy and neoglans formation, the IIEF-5, Quality of Erection Questionnaire (QEQ), Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) and Self-Esteem and Relationship (SEAR) were used. This study reported a high percentage of patient and partner satisfaction with surgical treatment and recovery of sexual function, selfesteem, and overall relationship satisfaction [206]. 7.2.6 Quality of life and sexual function after total penectomy In ten patients with penile cancer evaluated after total amputation of the penis, there were significant effects on sexual life and overall QoL, although there were no negative implications in terms of partner relationships, selfassessment or the evaluation of masculinity [207]. 7.2.7 Quality of life after partial penectomy Several qualitative and quantitative instruments have been used to assess ‘psychological behaviour and adjustment’ and ‘social activity’ as QoL indicators [204, 208]. Patient-reported fears were those of mutilation, loss of sexual pleasure and of cancer death and what this would mean for their families. The study reported no significant levels of anxiety and depression on the General Health Questionnaire-12 and the Hospital Anxiety and Depression Scale. ‘Social activity’ remained the same after surgery in terms of living conditions, family life and social interactions.

7.3

Total phallic reconstruction

There is very limited data about total phallic reconstruction following full or near-total penile amputation [137, 209, 210]. Although it is not possible to restore function without a penile prosthesis, cosmetically acceptable results can be obtained.

7.4

Specialised care

Since penile cancer is rare, patients should be referred to a centre with experience and expertise in local treatment, pathological diagnosis, chemotherapy and psychological support for penile cancer patients. Some countries have centralised the care of penile cancer patients (Sweden, Denmark, the Netherlands, the UK).

8.

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Stuiver, M.M., et al. Early wound complications after inguinal lymphadenectomy in penile cancer: a historical cohort study and risk-factor analysis. Eur Urol, 2013. 64: 486. https://www.ncbi.nlm.nih.gov/pubmed/23490726 Koifman, L., et al. Radical open inguinal lymphadenectomy for penile carcinoma: surgical technique, early complications and late outcomes. J Urol, 2013. 190: 2086. https://www.ncbi.nlm.nih.gov/pubmed/23770135 Yao, K., et al. Modified technique of radical inguinal lymphadenectomy for penile carcinoma: morbidity and outcome. J Urol, 2010. 184: 546. https://www.ncbi.nlm.nih.gov/pubmed/20620415 Hegarty, P.K., et al. Controversies in ilioinguinal lymphadenectomy. Urol Clin North Am, 2010. 37: 421. https://www.ncbi.nlm.nih.gov/pubmed/20674697 Protzel, C., et al. Lymphadenectomy in the surgical management of penile cancer. Eur Urol, 2009. 55: 1075. https://www.ncbi.nlm.nih.gov/pubmed/19264390 Thuret, R., et al. A contemporary population-based assessment of the rate of lymph node dissection for penile carcinoma. Ann Surg Oncol, 2011. 18: 439. https://www.ncbi.nlm.nih.gov/pubmed/20839061 La-Touche, S., et al. Trial of ligation versus coagulation of lymphatics in dynamic inguinal sentinel lymph node biopsy for staging of squamous cell carcinoma of the penis. Ann R Coll Surg Engl, 2012. 94: 344. https://www.ncbi.nlm.nih.gov/pubmed/22943231 Weldrick, C., et al. A comparison of fibrin sealant versus standard closure in the reduction of postoperative morbidity after groin dissection: A systematic review and meta-analysis. Eur J Surg Oncol, 2014. 40: 1391. https://www.ncbi.nlm.nih.gov/pubmed/25125341 Cui, Y., et al. Saphenous vein sparing during laparoscopic bilateral inguinal lymphadenectomy for penile carcinoma patients. Int Urol Nephrol, 2016. 48: 363. https://www.ncbi.nlm.nih.gov/pubmed/26660956 Kumar, V., et al. Prospective study comparing video-endoscopic radical inguinal lymph node dissection (VEILND) with open radical ILND (OILND) for penile cancer over an 8-year period. BJU Int, 2017. 119: 530. https://www.ncbi.nlm.nih.gov/pubmed/27628265 Tauber, R., et al. Inguinal lymph node dissection: epidermal vacuum therapy for prevention of wound complications. J Plast Reconstr Aesthet Surg, 2013. 66: 390. https://www.ncbi.nlm.nih.gov/pubmed/23107617 Lughezzani, G., et al. The relationship between characteristics of inguinal lymph nodes and pelvic lymph node involvement in penile squamous cell carcinoma: a single institution experience. J Urol, 2014. 191: 977. https://www.ncbi.nlm.nih.gov/pubmed/24262497 Tobias-Machado, M., et al. Video endoscopic inguinal lymphadenectomy: a new minimally invasive procedure for radical management of inguinal nodes in patients with penile squamous cell carcinoma. J Urol, 2007. 177: 953. https://www.ncbi.nlm.nih.gov/pubmed/17296386 Graafland, N.M., et al. Prognostic significance of extranodal extension in patients with pathological node positive penile carcinoma. J Urol, 2010. 184: 1347. https://www.ncbi.nlm.nih.gov/pubmed/20723934 Lucky, M.A., et al. Referrals into a dedicated British penile cancer centre and sources of possible delay. Sex Transm Infect, 2009. 85: 527. https://www.ncbi.nlm.nih.gov/pubmed/19584061 Nicolai, N., et al. A Combination of Cisplatin and 5-Fluorouracil With a Taxane in Patients Who Underwent Lymph Node Dissection for Nodal Metastases From Squamous Cell Carcinoma of the Penis: Treatment Outcome and Survival Analyses in Neoadjuvant and Adjuvant Settings. Clin Genitourin Cancer, 2016. 14: 323. https://www.ncbi.nlm.nih.gov/pubmed/26341040 Necchi, A., et al. Prognostic Factors of Adjuvant Taxane, Cisplatin, and 5-Fluorouracil Chemotherapy for Patients With Penile Squamous Cell Carcinoma After Regional Lymphadenectomy. Clin Genitourin Cancer, 2016. 14: 518. https://www.ncbi.nlm.nih.gov/pubmed/27050716

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Hakenberg, O.W., et al. Cisplatin, methotrexate and bleomycin for treating advanced penile carcinoma. BJU Int, 2006. 98: 1225. https://www.ncbi.nlm.nih.gov/pubmed/17125480 Haas, G.P., et al. Cisplatin, methotrexate and bleomycin for the treatment of carcinoma of the penis: a Southwest Oncology Group study. J Urol, 1999. 161: 1823. https://www.ncbi.nlm.nih.gov/pubmed/10332445 Hussein, A.M., et al. Chemotherapy with cisplatin and 5-fluorouracil for penile and urethral squamous cell carcinomas. Cancer, 1990. 65: 433. https://www.ncbi.nlm.nih.gov/pubmed/2297633 Shammas, F.V., et al. Cisplatin and 5-fluorouracil in advanced cancer of the penis. J Urol, 1992. 147: 630. https://www.ncbi.nlm.nih.gov/pubmed/1538445 Theodore, C., et al. A phase II multicentre study of irinotecan (CPT 11) in combination with cisplatin (CDDP) in metastatic or locally advanced penile carcinoma (EORTC PROTOCOL 30992). Ann Oncol, 2008. 19: 1304. https://www.ncbi.nlm.nih.gov/pubmed/18417462 Nicholson, S., et al. Phase II trial of docetaxel, cisplatin and 5FU chemotherapy in locally advanced and metastatic penis cancer (CRUK/09/001). Br J Cancer, 2013. 109: 2554. https://www.ncbi.nlm.nih.gov/pubmed/24169355 Eliason, M., et al. Primary treatment of verrucous carcinoma of the penis with fluorouracil, cisdiamino-dichloro-platinum, and radiation therapy. Arch Dermatol, 2009. 145: 950. https://www.ncbi.nlm.nih.gov/pubmed/19687438 Pond, G.R., et al. Prognostic risk stratification derived from individual patient level data for men with advanced penile squamous cell carcinoma receiving first-line systemic therapy. Urol Oncol, 2014. 32: 501. https://www.ncbi.nlm.nih.gov/pubmed/24332646 Di Lorenzo, G., et al. Cisplatin and 5-fluorouracil in inoperable, stage IV squamous cell carcinoma of the penis. BJU Int, 2012. 110: E661. https://www.ncbi.nlm.nih.gov/pubmed/22958571 Di Lorenzo, G., et al. Paclitaxel in pretreated metastatic penile cancer: final results of a phase 2 study. Eur Urol, 2011. 60: 1280. https://www.ncbi.nlm.nih.gov/pubmed/21871710 Power, D.G., et al. Cisplatin and gemcitabine in the management of metastatic penile cancer. Urol Oncol, 2009. 27: 187. https://www.ncbi.nlm.nih.gov/pubmed/18367122 Gou, H.F., et al. Epidermal growth factor receptor (EGFR)-RAS signaling pathway in penile squamous cell carcinoma. PLoS One, 2013. 8: e62175. https://www.ncbi.nlm.nih.gov/pubmed/23637996 Necchi, A., et al. Proof of activity of anti-epidermal growth factor receptor-targeted therapy for relapsed squamous cell carcinoma of the penis. J Clin Oncol, 2011. 29: e650. https://www.ncbi.nlm.nih.gov/pubmed/21632506 Carthon, B.C., et al. Epidermal growth factor receptor-targeted therapy in locally advanced or metastatic squamous cell carcinoma of the penis. BJU Int, 2014. 113: 871. https://www.ncbi.nlm.nih.gov/pubmed/24053151 Zhu, Y., et al. Feasibility and activity of sorafenib and sunitinib in advanced penile cancer: a preliminary report. Urol Int, 2010. 85: 334. https://www.ncbi.nlm.nih.gov/pubmed/20980789 Di Lorenzo, G., et al. Cytosolic phosphorylated EGFR is predictive of recurrence in early stage penile cancer patients: a retropective study. J Transl Med, 2013. 11: 161. https://www.ncbi.nlm.nih.gov/pubmed/23819610 Necchi, A., et al. Panitumumab Treatment for Advanced Penile Squamous Cell Carcinoma When Surgery and Chemotherapy Have Failed. Clin Genitourin Cancer, 2016. 14: 231. https://www.ncbi.nlm.nih.gov/pubmed/26362073 Horenblas, S., et al. Local recurrent tumour after penis-conserving therapy. A plea for long-term follow-up. Br J Urol, 1993. 72: 976. https://www.ncbi.nlm.nih.gov/pubmed/8306171 Kroon, B.K., et al. Patients with penile carcinoma benefit from immediate resection of clinically occult lymph node metastases. J Urol, 2005. 173: 816. https://www.ncbi.nlm.nih.gov/pubmed/15711276

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CONFLICT OF INTEREST

All members of the Penile Cancer Guidelines working group have provided disclosure statements of all relationships that they have that might be perceived as a potential source of a conflict of interest. This information is publicly accessible through the European Association of Urology website: http://uroweb.org/ guideline/penile-cancer/. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

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10. CITATION INFORMATION The format in which to cite the EAU Guidelines will vary depending on the style guide of the journal in which the citation appears. Accordingly, the number of authors or whether, for instance, to include the publisher, location, or an ISBN number may vary. The compilation of the complete Guidelines should be referenced as: EAU Guidelines. Edn. presented at the EAU Annual Congress Amsterdam, 2020. ISBN 978-94-92671-07-3. If a publisher and/or location is required, include: EAU Guidelines Office, Arnhem, The Netherlands. http://uroweb.org/guidelines/compilations-of-all-guidelines/ References to individual guidelines should be structured in the following way: Contributors’ names. Title of resource. Publication type. ISBN. Publisher and publisher location, year.

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EAU Guidelines on

Primary Urethral Carcinoma G. Gakis, J.A. Witjes (Chair), H.M. Bruins, R. Cathomas, E. Compérat, N.C. Cowan, J.A. Efstathiou, A.G. van der Heijden, V. Hernàndez, A. Lorch, M.I. Milowsky, M.J. Ribal (Vice-chair), G.N. Thalmann, E. Veskimäe Guidelines Associates: E.E. Linares Espinós, Y. Neuzillet, M. Rouanne

© European Association of Urology 2021

TABLE OF CONTENTS

PAGE

1. INTRODUCTION 1.1 Aims and scope 1.2 Panel composition 1.3 Available publications 1.4 Publication history & summary of changes 1.4.1 Summary of changes

4 4 4 4 4 4

2.

METHODS 2.1 Data identification 2.2 Review 2.3 Future goals

4 4 5 5

3.

EPIDEMIOLOGY, AETIOLOGY AND PATHOLOGY 3.1 Epidemiology 3.2 Aetiology 3.3 Histopathology

5 5 6 6

4.

STAGING AND CLASSIFICATION SYSTEMS 4.1 Tumour, Node, Metastasis (UICC/TNM) staging system 4.2 Tumour grade 4.3 Handling of tumour specimens 4.4 Guideline for staging and classification systems

6 6 7 7 8

5.

DIAGNOSTIC EVALUATION AND STAGING 5.1 History 5.2 Clinical examination 5.3 Urinary cytology 5.4 Diagnostic urethrocystoscopy and biopsy 5.5 Imaging for diagnosis and stagingg 5.6 Regional lymph nodes 5.7 Summary of evidence and guidelines for diagnostic evaluation and staging

8 8 8 8 8 8 9 9

6.

PROGNOSIS 6.1 Long-term survival after primary urethral carcinoma 6.2 Predictors of survival in primary urethral carcinoma 6.3 Summary of evidence for prognosis

9 9 9 9

7. DISEASE MANAGEMENT 7.1 Treatment of localised primary urethral carcinoma in males 7.1.1 Summary of evidence and guidelines for the treatment of localised primary urethral carcinoma in males 7.2 Treatment of localised urethral carcinoma in females 7.2.1 Urethrectomy and urethra-sparing surgery 7.2.2 Radiotherapy 7.2.3 Summary of evidence and guidelines for the treatment of localised urethral carcinoma in females 7.3 Multimodal treatment in locally advanced urethral carcinoma in both genders 7.3.1 Introduction 7.3.2 Preoperative cisplatin-based chemotherapy 7.3.3 Chemoradiotherapy in locally advanced squamous cell carcinoma of the urethra 7.3.4 Salvage treatment in recurrent primary urethral carcinoma after surgery for primary treatment 7.3.5 Treatment of regional lymph nodes 7.3.6 Summary of evidence and guidelines for multimodal treatment in advanced urethral carcinoma in both genders

2

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7.4 Treatment of urothelial carcinoma of the prostate 7.4.1 Summary of evidence and guidelines for the treatment of urothelial carcinoma of the prostate 7.5 Metastatic disease

12

8.

FOLLOW-UP

14

9.

REFERENCES

14

10.

CONFLICT OF INTEREST

18

11.

CITATION INFORMATION

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12 12

3

1.

INTRODUCTION

1.1

Aims and scope

The aim of these guidelines is to deliver current evidence-based information on the diagnosis and treatment of patients with primary urethral carcinoma. When the first carcinoma in the urinary tract is detected in the urethra, this is defined as primary urethral carcinoma, in contrast to secondary urethral carcinoma, which presents as recurrent carcinoma in the urethra after prior diagnosis and treatment of carcinoma elsewhere in the urinary tract. Most often, secondary urethral carcinoma is reported after radical cystectomy for bladder cancer [1, 2] (see Chapter 7.4 of the European Association of Urology [EAU] Guidelines on Muscle-invasive and Metastatic Bladder Cancer [MIBC]) [2]. It must be emphasised that clinical guidelines present the best evidence available to the experts but following guideline recommendations will not necessarily result in the best outcome. Guidelines can never replace clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions - also taking personal values and preferences/individual circumstances of patients into account. Guidelines are not mandates and do not purport to be a legal standard of care.

1.2

Panel composition

The EAU Guidelines Panel on MIBC is responsible for this publication. This is an international multidisciplinary group of clinicians, including urologists, oncologists, a pathologist, a radiotherapist and a radiologist. Members of this panel have been selected based on their expertise to represent the professionals treating patients suspected of suffering from urethral carcinoma. All experts involved in the production of this document have submitted potential conflict of interest statements, which can be viewed on the EAU Website Uroweb: https://uroweb.org/guideline/primary-urethral-carcinoma/.

1.3

Available publications

A quick reference document (Pocket guidelines) is available in print and as an app for iOS and Android devices, presenting the main findings of the Primary Urethral Carcinoma Guidelines. These are abridged versions which may require consultation together with the full text version. The most recent scientific summary was published in 2020 [3].

1.4

Publication history & summary of changes

The Primary Urethral Carcinoma Guidelines were first published in 2013. This is the eight update of this document. 1.4.1 Summary of changes The literature for the complete document has been assessed and updated, where relevant. In particular for: • Section 5.3 – Urinary cytology; • Section 5.5 – Imaging for diagnosis and staging; • Chapter 6 – Prognosis; • Section 7.3 – Multimodal treatment in locally advanced urethral carcinoma in both genders. A new recommendation was provided: 7.3.6 S  ummary of evidence and guidelines for multimodal treatment in advanced urethral carcinoma in both genders Recommendation Offer inguinal lymph node (LN) dissection to patients with limited LN-positive urethral squamous cell carcinoma.

2.

METHODS

2.1

Data identification

Strength rating Strong

For the 2021 Primary Urethral Carcinoma Guidelines, new and relevant evidence has been identified, collated, and appraised through a structured assessment of the literature. An updated systematic literature search was performed to identify studies reporting data on urethral malignancies since the prior search, covering a time frame between July 3rd, 2019 and October 20th, 2020. Databases searched included Ovid (Medline), EMBASE

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PRIMARY URETHRAL CARCINOMA - LIMITED UPDATE MARCH 2021

and the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews. A total of 117 unique records were identified, retrieved, and screened for relevance. Five new references were included in this 2021 publication. A detailed search strategy is available online: https://uroweb.org/guideline/primaryurethral-carcinoma/?type=appendices-publications. For each recommendation within the guidelines there is an accompanying online strength rating form, based on a modified GRADE methodology [4, 5]. These forms address a number of key elements namely: 1.

2. 3. 4. 5. 6.

the overall quality of the evidence which exists for the recommendation, references used in this text are graded according to a classification system modified from the Oxford Centre for Evidence-Based Medicine Levels of Evidence [6]; the magnitude of the effect (individual or combined effects); the certainty of the results (precision, consistency, heterogeneity and other statistical or study related factors); the balance between desirable and undesirable outcomes; the impact of patient values and preferences on the intervention; the certainty of those patient values and preferences.

These key elements are the basis which panels use to define the strength rating of each recommendation. The strength of each recommendation is represented by the words ‘strong’ or ‘weak’ [7]. The strength of each recommendation is determined by the balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including certainty of estimates), and nature and variability of patient values and preferences. The strength rating forms will be available online. Additional information can be found in the general Methodology section of this print, and online at the EAU website; http://www.uroweb.org/guideline/. A list of Associations endorsing the EAU Guidelines can also be viewed online at the above address.

2.2

Review

This document was peer-reviewed prior to publication in 2020.

2.3

Future goals

The MIBC Guidelines Panel aims to systematically address the following key clinical topics in future updates of the Primary Urethral Carcinoma Guidelines: • assessment of the accuracy of computed tomography [CT] and magnetic resonance imaging [MRI] for local staging of primary urethral carcinoma and their predictive value on clinical decision-making; • the (long-term) efficacy of urethral-sparing surgery and chemoradiotherapy for genital preservation in localised and locally advanced tumours; • the prognostic impact of neoadjuvant and adjuvant treatment modalities in locally advanced disease; • the prognostic impact of the extent of transurethral resection of the prostate prior to bacillus CalmetteGuérin (BCG) treatment in urothelial malignancies of the prostatic urethra and ducts; • the therapeutic benefit and clinical safety of programmed cell death (ligand)-1 inhibitors for the treatment of advanced primary urethral carcinoma; • the extent and prognostic benefit of regional Lymph node (LN) dissection at primary treatment.

3.

EPIDEMIOLOGY, AETIOLOGY AND PATHOLOGY

3.1

Epidemiology

Primary urethral carcinoma is considered a rare cancer, accounting for < 1% of all genitourinary malignancies [8] (ICD-O3 topography code: C68.0) [9]. In 2013, the prevalence of urethral carcinoma in the 28 European Union countries was 3,986 cases with an estimated annual incidence of 1,504 new cases, with a male/female prevalence of 2.9: 1 [10]. Likewise, in an analysis of the Surveillance, Epidemiology and End Results (SEER) database, the incidence of primary urethral carcinoma peaked in the > 75 years age group (7.6/million). The age-standardised rate was 4.3/million in men and 1.5/million in women and was almost negligible in those aged < 55 years (0.2/million) [11].

PRIMARY URETHRAL CARCINOMA - LIMITED UPDATE MARCH 2021

5

3.2

Aetiology

For male primary urethral carcinoma, various predisposing factors have been reported, including urethral strictures [12, 13], chronic irritation after intermittent catheterisation/urethroplasty [14-16], external beam irradiation therapy (EBRT) [17], radioactive seed implantation [18], chronic urethral inflammation/urethritis following sexually transmitted diseases (i.e., condylomata associated with human papilloma virus 16) [19, 20] and lichen sclerosis [13]. In female urethral carcinoma, urethral diverticula [21-23] and recurrent urinary tract infections [24] have been associated with primary urethral carcinoma. Mid-urethral sling meshes have not been associated with an increased risk of primary urethral carcinoma [25]. Clear-cell adenocarcinoma (AC) may also have a congenital origin [26, 27].

3.3

Histopathology

Both the Surveillance of Rare Cancers in Europe (RARECARE) project and SEER database have reported that urothelial carcinoma (UC) of the urethra is the predominant histological type of primary urethral cancer (54–65%), followed by squamous cell carcinoma (SCC) (16–22%) and AC (10–16%) [10, 28]. A SEER analysis of 2,065 men with primary urethral carcinoma (mean age 73 years) found that UC was most common (78%), and SCC (12%) and AC (5%) were significantly less frequent [29]. In women, AC is the more frequent histology (38–46.7%) followed by SCC (25.4–28%), UC (24.9–28%) and other histological entities (6%) [30, 31].

4.

STAGING AND CLASSIFICATION SYSTEMS

4.1

Tumour, Node, Metastasis (UICC/TNM) staging system

In men and women, urethral carcinoma is classified according to the 8th edition of the TNM classification [9] (Table 4.1). It should be noted that there is a separate TNM staging system for prostatic UC [9]. Of note, for cancers occurring in the urethral diverticulum, stage T2 is not applicable as urethral diverticula are lacking periurethral muscle [32]. Table 4.1: TNM classification (8th edition) for urethral carcinoma [9] T - Primary Tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour Urethra (male and female) Ta Non-invasive papillary, polypoid, or verrucous carcinoma Tis Carcinoma in situ T1 Tumour invades subepithelial connective tissue T2 Tumour invades any of the following: corpus spongiosum, prostate, periurethral muscle T3 Tumour invades any of the following: corpus cavernosum, beyond prostatic capsule, anterior vagina, bladder neck (extraprostatic extension) T4 Tumour invades other adjacent organs (invasion of the bladder) Urothelial (transitional cell) carcinoma of the prostate Tis pu Carcinoma in situ, involvement of prostatic urethra Tis pd Carcinoma in situ, involvement of prostatic ducts T1 Tumour invades subepithelial connective tissue (for tumours involving prostatic urethra only) T2 Tumour invades any of the following: prostatic stroma, corpus sponsiosum, periurethral muscle T3 Tumour invades any of the following: corpus cavernosum, beyond prostatic capsule, bladder neck (extraprostatic extension) T4 Tumour invades other adjacent organs (invasion of the bladder or rectum) N - Regional Lymph Nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single lymph node N2 Metastasis in multiple lymph nodes M - Distant Metastasis M0 No distant metastasis M1 Distant metastasis

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4.2

Tumour grade

The former World Health Organization (WHO) grading system of 1973, which differentiated urothelial carcinomas into three different grades (G1-G3), has been replaced by the grading system in 2004 [33]. Nonurothelial urethral carcinoma is graded by a trinomial system that differentiates between well-differentiated (G1), moderately-differentiated (G2), and poorly-differentiated tumours (G3). Table 4.2 lists the different grading systems according to the WHO 1973 and 2004 systems [33]. The 2004 classification corresponds to the new 2016 WHO classification [34]. Table 4.2: Histopathological grading of urothelial and non-urothelial primary urethral carcinoma [33] Urothelial urethral carcinoma PUNLMP Low grade High grade

Papillary urothelial neoplasm of low malignant potential Well differentiated Poorly differentiated

Non-urothelial urethral carcinoma Gx G1 G2 G3

Tumour grade not assessable Well differentiated Moderately differentiated Poorly differentiated

4.3

Handling of tumour specimens

Specimen handling should follow the general rules as published by the International Collaboration on Cancer Reporting [35]. Table 4.3: Required and recommended elements for pathology reporting of carcinoma of the urethra in urethrectomy specimens [9, 35] Required Operative procedure

Additional specimens submitted Maximum tumour dimension

Macroscopic tumour site Macroscopic extent of invasion Histological tumour type

Recommended

Clinical information

Cannot be assessed No macroscopically visible tumour Maximum tumour dimension (largest tumour)

Histological subtype/ variant (urothelial carcinoma)

Non-invasive carcinoma Histological tumour grade Microscopic extent of invasion Lymphovascular invasion Margin status Regional lymph node No regional lymph nodes status submitted

Previous history of urinary tract disease or distant metastasis Previous therapy Other clinical information

Tumour focality Other tumour dimensions (than maximum dimension) of the largest tumour Block identification key Associated epithelial lesions Extranodal spread for involved regional lymph node(s) Coexistent pathology Ancillary studies

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4.4

Guideline for staging and classification systems

Recommendation Use the 2017 TNM classification and 2004/2016 WHO grading systems for pathological staging and grading of primary urethral carcinoma.

Strength rating Strong

5.

DIAGNOSTIC EVALUATION AND STAGING

5.1

History

When becoming clinically apparent, most patients (45–57%) with primary urethral carcinoma present with symptoms associated with locally advanced disease (T3/T4) [36]. At initial presentation visible haematuria or bloody urethral discharge is reported in up to 62% of the cases. Further symptoms of locally advanced disease include; an extra-urethral mass (52%), bladder outlet obstruction (48%), pelvic pain (33%), urethrocutaneous fistula (10%), abscess formation (5%) or dyspareunia [36].

5.2

Clinical examination

In men, physical examination should comprise palpation of the external genitalia for suspicious indurations or masses and digital rectal examination [37]. In women, further pelvic examination with careful inspection and palpation of the urethra should be performed, especially in those with primary onset of irritative or obstructive voiding. In addition, bimanual examination, when necessary under general anaesthesia, should be performed for local clinical staging and to exclude the presence of colorectal or gynaecological malignancies. Bilateral inguinal palpation should be conducted to assess the presence of enlarged LNs, describing location, size, and mobility [38].

5.3

Urinary cytology

Cytological assessment of urine specimens in suspect cases of primary urethral carcinoma should be conducted according to the Paris system [39]. The role of urinary cytology in primary urethral carcinoma is limited since its sensitivity ranges between 55% and 59% [40]. Detection rates depend on the underlying histological entity. In male patients, the sensitivity for UC and SCC was reported to be 80% and 50%, respectively, whereas in female patients, sensitivity was found to be 77% for SCC and 50% for UC [40].

5.4

Diagnostic urethrocystoscopy and biopsy

Diagnostic urethrocystoscopy and biopsy enables primary assessment of a urethral tumour in terms of tumour extent, location, and underlying histology [37]. To enable accurate pathological assessment of surgical margins, biopsy sites (proximal/distal end) should be marked and sent together with clinical information to the pathologist. To obtain all relevant information, the collection, handling, and evaluation of biopsy specimen should follow the recommendations provided by the International Collaboration on Cancer Reporting (see Table 4.3) [35]. Careful cystoscopic examination is necessary to exclude the presence of concomitant bladder tumours [41]. A cold-cup biopsy enables accurate tissue retrieval for histological analysis and avoids artificial tissue damage. In patients with larger lesions, transurethral resection (optionally in men under penile blood arrest using a tourniquet) can be performed for histological diagnosis [42]. In patients with suspected UC of the prostatic urethra or ducts, resectoscope loop biopsy of the prostatic urethra (between the five and seven o’clock position from the bladder neck and distally around the area of the verumontanum) can contribute to an improved detection rate [43].

5.5

Imaging for diagnosis and stagingg

Radiological imaging of urethral carcinoma aims to assess local tumour extent and to detect lymphatic and distant metastatic spread. In a recent multicentre study, the accuracy of CT for clinical tumour and nodal staging predicting final pathological staging was found to be 72.9% and 70.6%, respectively [44]. Magnetic resonance imaging can be used to evaluate local tumour extent and presence of regional LN metastases, focusing in particular on inguinal and pelvic LNs [45-47]. Computed tomography can be used for distant staging and concentrate on chest, abdomen, and pelvis, with CT of the thorax and abdomen in all patients with invasive disease (> cT1N0M0) [48]. If imaging of the remainder of the urothelium is required, CT urography should be performed [49]. For local staging, there is evidence that MRI is an accurate tool for monitoring tumour response to neoadjuvant chemoradiotherapy and evaluating the extent of local disease prior to exenterative surgery [50].

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5.6

Regional lymph nodes

In urethral carcinoma, in contrast to penile cancer (41%) [51], enlarged LNs often represent metastatic disease (84%) [52-54]. In men, lymphatics from the anterior urethra drain into the superficial- and deep inguinal LNs and, subsequently, to the pelvic (external, obturator and internal iliac) LNs. Conversely, lymphatic vessels of the posterior urethra drain into the pelvic LNs. In women, the lymph of the proximal third drains into the pelvic LN chains, whereas the distal two-thirds initially drain into the superficial- and deep inguinal nodes [55, 56].

5.7

Summary of evidence and guidelines for diagnostic evaluation and staging

Summary of evidence Patients with clinically enlarged inguinal or pelvic LNs often exhibit pathological LN metastasis.

Recommendations Use urethrocystoscopy with biopsy and urinary cytology to diagnose urethral carcinoma. Assess the presence of distant metastases by computed tomography of the thorax and abdomen/pelvis. Use pelvic magnetic resonance imaging to assess the local extent of urethral tumour and regional lymph node enlargement.

6.

PROGNOSIS

6.1

Long-term survival after primary urethral carcinoma

LE 3

Strength rating Strong Strong Strong

According to the RARECARE project, the one- and 5-year relative overall survival (OS) rates in patients with urethral carcinoma in Europe are 71% and 54%, respectively [10]. Based on longer follow-up, an analysis of the SEER database, comparing prognostic factors in rare pathological types of primary urethral carcinoma (n = 257) and common pathological groups (n = 2,651), reported 10-year OS rates of 42.4% and 31.9%, respectively [57]. Cancer-specific survival (CSS) rates at five and ten years were 68% and 60%, respectively [11]. Age (> 60 years), race (others vs. whites), T-stage (T3/T4 vs. Ta-T2) and M-stage (M1 vs. M0) were independent prognostic risk factors for OS and CSS in rare pathological variants [57].

6.2

Predictors of survival in primary urethral carcinoma

In Europe, 5-year OS rate does not substantially differ between the sexes [10, 31]. Prognostic factors of decreased survival in patients with primary urethral carcinoma are: • advanced age (> 65 years) and black race [10, 31, 58, 59]; • stage, grade, nodal involvement [53, 59] and metastasis [29]; • tumour size and proximal tumour location [29]; • extent of surgical treatment and treatment modality [29, 58, 59]; • underlying histology [10, 29, 58-60]; • presence of concomitant bladder cancer [41]; • location of recurrence (urethral vs. non-urethral) [61]. Some limitations have to be considered when interpreting these results. In the Dutch study, the numbers were low (n = 91) [60]. .

6.3

Summary of evidence for prognosis

Summary of evidence Prognostic factors for survival in primary urethral carcinoma are: age, race, tumour stage and grade, nodal stage, presence of distant metastasis, histological type, tumour size, tumour location, concomitant bladder cancer and type and modality of treatment.

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LE 3

9

7.

DISEASE MANAGEMENT

7.1

Treatment of localised primary urethral carcinoma in males

Previously, treatment of male distal urethral carcinoma followed the procedure for penile cancer, with aggressive surgical excision of the primary lesion with a wide safety margin [37]. Distal urethral tumours exhibit significantly improved survival rates compared with proximal tumours [62]. Therefore, optimising treatment of distal urethral carcinoma has become the focus of clinicians to improve functional outcome and quality of life (QoL), while preserving oncological safety. A retrospective series found no evidence of local recurrence, even with < 5 mm resection margins (median follow-up: 17–37 months), in men with pT1-3N0-2 distal urethral carcinoma treated with well-defined penis-preserving surgery and additional iliac/inguinal lymphadenectomy (LND) for clinically suspected LN disease [63]. Similar results for the feasibility of penile-preserving surgery have also been reported in recent series [64, 65]. However, a series on patients treated with penis-preserving surgery for distal urethral carcinoma reported a higher risk of progression in patients with positive proximal margins, which was also more frequently observed in cases with lymphovascular and peri-neural invasion of the primary tumour [66]. 7.1.1

Summary of evidence and guidelines for the treatment of localised primary urethral carcinoma in males

Summary of evidence In distal urethral tumours performing a partial urethrectomy with a minimal safety margin does not increase the risk of local recurrence. Recommendations Offer distal urethrectomy as an alternative to penile amputation in localised distal urethral tumours, if surgical margins are negative. Ensure complete circumferential assessment of the proximal urethral margin if penispreserving surgery is intended.

7.2

LE 3

Strength rating Weak Strong

Treatment of localised urethral carcinoma in females

7.2.1 Urethrectomy and urethra-sparing surgery In women with localised urethral carcinoma, to provide the highest chance of local cure, primary radical urethrectomy should remove all the peri-urethral tissue from the bulbocavernosus muscle bilaterally and distally, with a cylinder of all adjacent soft tissue up to the pubic symphysis and bladder neck. Bladder neck closure and appendicovesicostomy for primary distal urethral lesions has been shown to provide satisfactory functional results in women [37]. Previous series have reported outcomes in women with mainly distal urethral tumours undergoing primary treatment with urethra-sparing surgery with or without additional radiotherapy (RT) compared to primary urethrectomy, with the aim of maintaining integrity and function of the lower urinary tract [67, 68]. In longer-term series with a median follow-up of 153–175 months, local recurrence rates in women undergoing partial urethrectomy with intraoperative frozen section analysis were 22–60%, and distal sleeve resection of > 2 cm resulted in secondary urinary incontinence in 42% of patients who subsequently required additional reconstructive surgery [67, 68]. Ablative surgical techniques, i.e., transurethral resection (TUR) or laser, used for small distal urethral tumours, have also resulted in considerable local failure rates of 16%, with a CSS rate of 50%. This emphasises the critical role of local tumour control in women with distal urethral carcinoma to prevent local and systemic progression [67]. 7.2.2 Radiotherapy In women, RT was investigated in several older series with a medium follow up of 91–105 months [69]. With a median cumulative dose of 65 Gy (range 40–106 Gy), the 5-year local control rate was 64% and 7-year CSS was 49% [69]. Most local failures (95%) occurred within the first two years after primary treatment [69]. The extent of urethral tumour involvement was found to be the only parameter independently associated with local tumour control but the type of RT (EBRT vs. interstitial brachytherapy) was not [69]. In one study, the addition of brachytherapy to EBRT reduced the risk of local recurrence by a factor of 4.2 [70]. Of note, pelvic toxicity in those achieving local control was considerable (49%), including urethral stenosis, fistula, necrosis, cystitis and/or haemorrhage, with 30% of the reported complications graded as severe [69].

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7.2.3

Summary of evidence and guidelines for the treatment of localised urethral carcinoma in females

Summary of evidence In distal tumours, urethra-sparing surgery and local RT represent alternatives to primary urethrectomy but are associated with increased risk of tumour recurrence and local toxicity.

Recommendations Offer urethra-sparing surgery, as an alternative to primary urethrectomy, to women with distal urethral tumours, if negative surgical margins can be achieved intraoperatively. Offer local radiotherapy, as an alternative to urethral surgery, to women with localised urethral tumours, but discuss local toxicity.

7.3

LE 3

Strength rating Weak Weak

Multimodal treatment in locally advanced urethral carcinoma in both genders

7.3.1 Introduction Multimodal therapy in primary urethral carcinoma consists of definitive surgery plus chemotherapy with additional RT [71]. Multimodal therapy was often underutilised (16%) in locally advanced disease notwithstanding promising results [71-74]. In a recent study monotherapy was associated with decreased local recurrence-free survival after adjusting for stage, histology, sex, and year of treatment (p = 0.017). Its use has decreased over time [75]. 7.3.2 Preoperative cisplatin-based chemotherapy Retrospective studies have reported that modern cisplatin-based combination chemotherapy regimens can be effective in advanced primary urethral carcinoma providing prolonged survival even in LN-positive disease. Moreover, they have emphasised the critical role of surgery after chemotherapy to achieve long-term survival in patients with locally advanced urethral carcinoma. In a series of 124 patients, 39 (31%) were treated with peri-operative platinum-based chemotherapy for advanced primary urethral carcinoma (twelve patients received neoadjuvant chemotherapy, six received neoadjuvant chemoradiotherapy and 21 adjuvant chemotherapy). Patients who received neoadjuvant chemotherapy or chemoradiotherapy for locally advanced primary urethral carcinoma (≥ cT3 and/or cN+) appeared to demonstrate improved survival compared to those who underwent upfront surgery with or without adjuvant chemotherapy [76]. Another retrospective series including 44 patients with advanced primary urethral carcinoma, reported outcomes on 21 patients who had preoperatively received cisplatin-based combination chemotherapy according to the underlying histologic subtype. The overall response rate for the various regimens was 72% and the median OS 32 months [52]. 7.3.3 Chemoradiotherapy in locally advanced squamous cell carcinoma of the urethra The clinical feasibility of local RT with concurrent chemotherapy as an alternative to surgery in locally advanced SCC has been reported in several series. This approach offers a potential for genital preservation [77-81]. The largest, and recently updated, retrospective series reported outcomes in 25 patients with primary locally advanced SCC of the urethra treated with two cycles of 5-fluorouracil and mitomycin C with concurrent EBRT. A complete response to primary chemoradiotherapy was observed in ~80% of patients. The 5-year OS and disease-specific survival was 52% and 68%, respectively. In this updated series, salvage surgery, initiated only in non-responders or in case of local failure, was not reported to be associated with improved survival [77]. A large retrospective cohort study in patients with locally advanced urethral carcinoma treated with adjuvant RT and surgery vs. surgery alone demonstrated that the addition of RT improved OS [82]. Salvage treatment in recurrent primary urethral carcinoma after surgery for primary treatment A multicentre study reported that patients who were treated with surgery as primary therapy and underwent surgery or RT-based salvage treatment for recurrent solitary or concomitant urethral disease, demonstrated similar survival rates compared to patients who never developed recurrence after primary treatment [61]. 7.3.4

7.3.5 Treatment of regional lymph nodes Nodal control in urethral carcinoma can be achieved either by regional LN dissection [37], RT [69] or chemotherapy [52]. Currently, there is still no clear evidence supporting prophylactic bilateral inguinal and/or pelvic LND in all patients with urethral carcinoma [54]. However, in patients with clinically enlarged inguinal/

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pelvic LNs or invasive tumours, regional LND should be considered as initial treatment since cure might still be achievable with limited disease [37]. It was recently shown that in patients with invasive urethral SCC and cN1-2 disease, inguinal LND conferred an OS benefit [54]. 7.3.6

Summary of evidence and guidelines for multimodal treatment in advanced urethral carcinoma in both genders

Summary of evidence In locally advanced urethral carcinoma, cisplatin-based chemotherapy with curative intent prior to surgery might improve survival compared to chemotherapy alone, or surgery followed by chemotherapy. In locally advanced SCC of the urethra, treatment with chemoradiotherapy might be an alternative to surgery.

Recommendations Discuss treatment of patients with locally advanced urethral carcinoma within a multidisciplinary team of urologists, radio-oncologists, and oncologists. In locally advanced urethral carcinoma, use cisplatin-based chemotherapeutic regimens with curative intent prior to surgery. In locally advanced squamous cell carcinoma (SCC) of the urethra, offer the combination of curative radiotherapy (RT) with radiosensitising chemotherapy for definitive treatment and genital preservation. Offer salvage surgery or RT to patients with urethral recurrence after primary treatment. Offer inguinal lymph node (LN) dissection to patients with limited LN-positive urethral SCC.

7.4

LE 3

3

Strength rating Strong Weak Weak

Weak Weak

Treatment of urothelial carcinoma of the prostate

Local conservative treatment with extensive TUR and subsequent BCG instillation is effective in patients with Ta or Tis prostatic urethral carcinoma [83]. Likewise, patients undergoing TUR of the prostate prior to BCG experience improved complete response rates compared with those who do not (95% vs. 66%) [84]. Risk of understaging local extension of prostatic urethral cancer at TUR is high in patients with ductal or stromal involvement [85]. In smaller series, response rates to BCG in patients with prostatic duct involvement have been reported to vary between 57% and 75% [83, 86]. Some earlier series have reported superior oncological results for the initial use of radical cystoprostatectomy as a primary treatment option in patients with ductal involvement [87, 88]. In 24 patients with prostatic stromal invasion treated with radical cystoprostatectomy, a LN mapping study found that twelve patients had positive LNs, with an increased proportion located above the iliac bifurcation [89]. 7.4.1

Summary of evidence and guidelines for the treatment of urothelial carcinoma of the prostate

Summary of evidence Patients undergoing TUR of the prostate for prostatic urothelial carcinoma prior to BCG treatment show superior complete response rates compared to those who do not.

Recommendations Offer a urethra-sparing approach with transurethral resection (TUR) and bacillus-Calmette Guérin (BCG) to patients with non-invasive urethral carcinoma or carcinoma in situ of the prostatic urethra and prostatic ducts. In patients not responding to BCG, or in patients with extensive ductal or stromal involvement, perform a cystoprostatectomy with extended pelvic lymphadenectomy.

7.5

LE 3

Strength rating Strong

Weak

Metastatic disease

There is no data addressing management of metastatic disease in primary urethral carcinoma patients. Systemic therapy in metastatic disease should be selected based on the histology of the tumour. The EAU Guidelines on Metastatic Bladder Cancer can be followed if UC is the predominant histology [2]. Even though urethral carcinoma patients have been included in large clinical trials on immunotherapy, so far, in terms of response rates, no subgroup analyses are available [90].

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PRIMARY URETHRAL CARCINOMA - LIMITED UPDATE MARCH 2021

In addition, there is an urgent clinical need to better address the role of local palliative treatment strategies in primary urethral carcinoma including surgery, which has shown to impact positively on QoL aspects in selected patients with advanced genital cancers [91].

SALVAGE SURGERY/RADIOTHERAPY

• Systemic therapy according to underlying histology T3-T4 N1-N2 • Inducve chemotherapy and consolidave surgery*** or • Chemoradiotherapy**

LOCAL RECURRENCE

FEMALE • Urethra-sparing surgery* or • Urethrectomy or •Radiotherapy

MALE • Distal urethrectomy*

T3-T4 N0 • Neoadjuvant chemotherapy and surgery or • Chemoradiotherapy** or • Surgery and adjuvant radiotherapy Proximal T2 • Urethrectomy **** (paral * or complete) Proximal Ta-T1 • Urethrectomy (paral * or complete) Prostac T2 +/- Proximal Ta-T2 • Radicalcystoprostatectomy and urethrectomy and lymphadenectomy **** Prostac Ta-Tis-T1 • Repeat TUR + BCG *****

LOCALISED (≤ T2 N0M0)

PUC DIAGNOSIS • Urethrocystoscopy • Biopsy/TUR • Urinary cytology

Distal Ta-T2

LOCALLY ADVANCED (T3-T4 N0-2 M0)

PUC STAGING • Pelvic MRI • Chest/abdomen CT

DISTANT METASTASIS

Figure 7.1: Management of primary urethral carcinoma

*

Ensure complete circumferential assessment if penis-preserving/urethra-sparing surgery or partial urethrectomy is intended. ** Squamous cell carcinoma. *** Regional lymphadenectomy should be considered in clinically enlarged lymph nodes. **** Consider neoadjuvant chemotherapy. ***** In extensive or BCG-unresponsive disease: consider (primary) cystoprostatectomy +/- urethrectomy + lymphadenectomy. BCG = bacillus Calmette-Guérin; CT = computed tomography; MRI = magnetic resonance imaging; PUC = primary urethral carcinoma; TUR = transurethral resection.

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8.

FOLLOW-UP

Given the low incidence of primary urethral carcinoma, follow-up has not been systematically investigated. Therefore, it seems reasonable to tailor surveillance regimens to patients’ individual risk factors (see Section 6.2). In patients undergoing urethra-sparing surgery, it seems prudent to advocate a more extensive follow-up with urinary cytology, urethrocystoscopy and cross-sectional imaging despite the lack of specific data.

9.

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Barkan, G.A., et al. The Paris System for Reporting Urinary Cytology: The Quest to Develop a Standardized Terminology. Acta Cytol, 2016. 60: 185. https://pubmed.ncbi.nlm.nih.gov/27318895 Touijer, A.K., et al. Role of voided urine cytology in diagnosing primary urethral carcinoma. Urology, 2004. 63: 33. https://pubmed.ncbi.nlm.nih.gov/14751342 Gakis, G., et al. Oncological Outcomes of Patients with Concomitant Bladder and Urethral Carcinoma. Urol Int, 2016. 97: 134. https://pubmed.ncbi.nlm.nih.gov/27462702 Samm, B.J., et al. Penectomy: a technique to reduce blood loss. Urology, 1999. 53: 393. https://pubmed.ncbi.nlm.nih.gov/9933061 Donat, S.M., et al. The efficacy of transurethral biopsy for predicting the long-term clinical impact of prostatic invasive bladder cancer. J Urol, 2001. 165: 1580. https://pubmed.ncbi.nlm.nih.gov/11342921 Schubert, T., et al. MP11-20 The predictive accuracy between clinical staging and pathological staging in patients with primary urethral carcinoma. J Urol, 2019. 201: e135. https://www.auajournals.org/doi/abs/10.1097/01.JU.0000555184.87550.3c Del Gaizo, A., et al. Magnetic resonance imaging of solid urethral and peri-urethral lesions. Insights Imaging, 2013. 4: 461. https://pubmed.ncbi.nlm.nih.gov/23686749 Itani, M., et al. MRI of female urethra and periurethral pathologies. Int Urogynecol J, 2016. 27: 195. https://pubmed.ncbi.nlm.nih.gov/26209954 Stewart, S.B., et al. Imaging tumors of the penis and urethra. Urol Clin North Am, 2010. 37: 353. https://pubmed.ncbi.nlm.nih.gov/20674692 Kim, B., et al. Imaging of the male urethra. Semin Ultrasound CT MR, 2007. 28: 258. https://pubmed.ncbi.nlm.nih.gov/17874650 Raman, S.P., et al. Upper and Lower Tract Urothelial Imaging Using Computed Tomography Urography. Radiol Clin North Am, 2017. 55: 225. https://pubmed.ncbi.nlm.nih.gov/28126213 Gourtsoyianni, S., et al. MRI at the completion of chemoradiotherapy can accurately evaluate the extent of disease in women with advanced urethral carcinoma undergoing anterior pelvic exenteration. Clin Radiol, 2011. 66: 1072. https://pubmed.ncbi.nlm.nih.gov/21839430 Naumann, C.M., et al. Reliability of dynamic sentinel node biopsy combined with ultrasound-guided removal of sonographically suspicious lymph nodes as a diagnostic approach in patients with penile cancer with palpable inguinal lymph nodes. Urol Oncol, 2015. 33: 389.e9. https://pubmed.ncbi.nlm.nih.gov/25934562 Dayyani, F., et al. Retrospective analysis of survival outcomes and the role of cisplatin-based chemotherapy in patients with urethral carcinomas referred to medical oncologists. Urol Oncol, 2013. 31: 1171. https://pubmed.ncbi.nlm.nih.gov/22534087 Gakis, G., et al. Prognostic factors and outcomes in primary urethral cancer: results from the international collaboration on primary urethral carcinoma. World J Urol, 2016. 34: 97. https://pubmed.ncbi.nlm.nih.gov/25981402 Werntz, R.P., et al. The role of inguinal lymph node dissection in men with urethral squamous cell carcinoma. Urol Oncol, 2018. 36: 526 e1. https://pubmed.ncbi.nlm.nih.gov/30446445 Carroll, P.R., et al. Surgical anatomy of the male and female urethra. Urol Clin North Am, 1992. 19: 339. https://pubmed.ncbi.nlm.nih.gov/1574824 Sharp, D., et al., Surgery of penile and urethral carcinoma, in Campbell’s Urology, D. McDougal, A. Wein, L. Kavoussi, A. Novick, A. Partin, C. Peters & P. Ramchandani, Editors. 212, Saunders Elsevier: Philadelphia, PA, USA. https://www.researchgate.net/publication/289837938_Surgery_of_Penile_and_Urethral_Carcinoma Abudurexiti, M., et al. Prognosis of rare pathological primary urethral carcinoma. Cancer Manag Res, 2018. 10: 6815. https://pubmed.ncbi.nlm.nih.gov/30584373 Champ, C.E., et al. Prognostic factors and outcomes after definitive treatment of female urethral cancer: a population-based analysis. Urology, 2012. 80: 374. https://pubmed.ncbi.nlm.nih.gov/22857759

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60.

61.

62. 63. 64.

65.

66.

67.

68.

69.

70.

71.

72.

73. 74.

75.

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Zi, H., et al. Nomograms for predicting long-term overall survival and cancer-specific survival in patients with primary urethral carcinoma: a population-based study. Int Urol Nephrol, 2020. 52: 287. https://pubmed.ncbi.nlm.nih.gov/31612421 Derksen, J.W., et al. Primary urethral carcinoma in females: an epidemiologic study on demographical factors, histological types, tumour stage and survival. World J Urol, 2013. 31: 147. https://pubmed.ncbi.nlm.nih.gov/22614443 Gakis, G., et al. The prognostic effect of salvage surgery and radiotherapy in patients with recurrent primary urethral carcinoma. Urol Oncol, 2018. 36: 10 e7. http://ascopubs.org/doi/abs/10.1200/jco.2015.33.15_suppl.4568 Dalbagni, G., et al. Male urethral carcinoma: analysis of treatment outcome. Urology, 1999. 53: 1126. https://pubmed.ncbi.nlm.nih.gov/10367840 Smith, Y., et al. Penile-preserving surgery for male distal urethral carcinoma. BJU Int, 2007. 100: 82. https://pubmed.ncbi.nlm.nih.gov/17488307 Pedrosa, J.A., et al. Distal urethrectomy for localized penile squamous carcinoma in situ extending into the urethra: an updated series. Int Urol Nephrol, 2014. 46: 1551. https://pubmed.ncbi.nlm.nih.gov/24633698 Kulkarni, M., et al. MP10-16 Substitution urethroplasty for treatment of distal urethral carcinoma and carcinoma in situ. J. Urol 193: e117. https://www.jurology.com/article/S0022-5347(15)00728-4/fulltext Torbrand, C., et al. Diagnosing Distal Urethral Carcinomas in Men Might Be Only the Tip of the Iceberg. Clin Genitourin Cancer, 2017. 15: e1131. https://pubmed.ncbi.nlm.nih.gov/28784424 Dimarco, D.S., et al. Surgical treatment for local control of female urethral carcinoma. Urol Oncol, 2004. 22: 404. https://pubmed.ncbi.nlm.nih.gov/15464921 DiMarco, D.S., et al. Outcome of surgical treatment for primary malignant melanoma of the female urethra. J Urol, 2004. 171: 765. https://pubmed.ncbi.nlm.nih.gov/14713806 Garden, A.S., et al. Primary carcinoma of the female urethra. Results of radiation therapy. Cancer, 1993. 71: 3102. https://pubmed.ncbi.nlm.nih.gov/8490839 Milosevic, M.F., et al. Urethral carcinoma in women: results of treatment with primary radiotherapy. Radiother Oncol, 2000. 56: 29. https://pubmed.ncbi.nlm.nih.gov/10869752 Zinman, L.N., et al. Management of Proximal Primary Urethral Cancer: Should Multidisciplinary Therapy Be the Gold Standard? Urol Clin North Am, 2016. 43: 505. https://pubmed.ncbi.nlm.nih.gov/27717436 Cahn, D.B., et al. Contemporary practice patterns and survival outcomes for locally advanced urethral malignancies: A National Cancer Database Analysis. Urol Oncol, 2017. 35: 670 e15. https://pubmed.ncbi.nlm.nih.gov/28803701 Dayyani, F., et al. Management of advanced primary urethral carcinomas. BJU Int, 2014. 114: 25. https://pubmed.ncbi.nlm.nih.gov/24447439 Peyton, C.C., et al. Survival Outcomes Associated With Female Primary Urethral Carcinoma: Review of a Single Institutional Experience. Clin Genitourin Cancer, 2018. 16: e1003. https://pubmed.ncbi.nlm.nih.gov/29859736 Mano, R., et al. Primary urethral cancer: treatment patterns and associated outcomes. BJU Int, 2020. 126: 359. https://pubmed.ncbi.nlm.nih.gov/32336001 Gakis, G., et al. Impact of perioperative chemotherapy on survival in patients with advanced primary urethral cancer: results of the international collaboration on primary urethral carcinoma. Ann Oncol, 2015. 26: 1754. https://pubmed.ncbi.nlm.nih.gov/25969370 Kent, M., et al. Combined chemoradiation as primary treatment for invasive male urethral cancer. J Urol, 2015. 193: 532. https://pubmed.ncbi.nlm.nih.gov/25088950 Gakis, G. Editorial Comment to Docetaxel, cisplatin and 5-fluorouracil chemotherapy with concurrent radiation for unresectable advanced urethral carcinoma. Int J Urol, 2014. 21: 424. https://pubmed.ncbi.nlm.nih.gov/24251884

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80.

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86. 87.

88.

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Itoh, J., et al. Docetaxel, cisplatin and 5-fluorouracil chemotherapy with concurrent radiation for unresectable advanced urethral carcinoma. Int J Urol, 2014. 21: 422. https://pubmed.ncbi.nlm.nih.gov/24251859 Hara, I., et al. Successful treatment for squamous cell carcinoma of the female urethra with combined radio- and chemotherapy. Int J Urol, 2004. 11: 678. https://pubmed.ncbi.nlm.nih.gov/15285764 Cohen, M.S., et al. Coordinated chemoradiation therapy with genital preservation for the treatment of primary invasive carcinoma of the male urethra. J Urol, 2008. 179: 536. https://pubmed.ncbi.nlm.nih.gov/18076921 Son, C.H., et al. Optimizing the Role of Surgery and Radiation Therapy in Urethral Cancer Based on Histology and Disease Extent. Int J Radiat Oncol Biol Phys, 2018. 102: 304. https://pubmed.ncbi.nlm.nih.gov/29908944 Palou Redorta, J., et al. Intravesical instillations with bacillus calmette-guerin for the treatment of carcinoma in situ involving prostatic ducts. Eur Urol, 2006. 49: 834. https://pubmed.ncbi.nlm.nih.gov/16426729 Gofrit, O.N., et al. Prostatic urothelial carcinoma: is transurethral prostatectomy necessary before bacillus Calmette-Guerin immunotherapy? BJU Int, 2009. 103: 905. https://pubmed.ncbi.nlm.nih.gov/19021623 Njinou Ngninkeu, B., et al. Transitional cell carcinoma involving the prostate: a clinicopathological retrospective study of 76 cases. J Urol, 2003. 169: 149. https://pubmed.ncbi.nlm.nih.gov/12478124 Palou, J., et al. Urothelial carcinoma of the prostate. Urology, 2007. 69: 50. https://pubmed.ncbi.nlm.nih.gov/17280908 Hillyard, R.W., Jr., et al. Superficial transitional cell carcinoma of the bladder associated with mucosal involvement of the prostatic urethra: results of treatment with intravesical bacillus Calmette-Guerin. J Urol, 1988. 139: 290. https://pubmed.ncbi.nlm.nih.gov/3339727 Solsona, E., et al. The prostate involvement as prognostic factor in patients with superficial bladder tumors. J Urol, 1995. 154: 1710. https://pubmed.ncbi.nlm.nih.gov/7563328 Vazina, A., et al. Stage specific lymph node metastasis mapping in radical cystectomy specimens. J Urol, 2004. 171: 1830. https://pubmed.ncbi.nlm.nih.gov/15076287 Balar, A.V., et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol, 2017. 18: 1483. https://pubmed.ncbi.nlm.nih.gov/28967485 Shukla, C.J., et al. Palliation of male genital cancers. Clin Oncol (R Coll Radiol), 2010. 22: 747. https://pubmed.ncbi.nlm.nih.gov/20800458

10. CONFLICT OF INTEREST All members of the Muscle-invasive and Metastatic Bladder Cancer Guidelines Panel have provided disclosure statements of all relationships that they have that might be perceived as a potential source of a conflict of interest. This information is open access available on the European Association of Urology website: http://www.uroweb.org/guidelines/primary-urethral-carcinoma/. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

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11. CITATION INFORMATION The format in which to cite the EAU Guidelines will vary depending on the style guide of the journal in which the citation appears. Accordingly, the number of authors or whether, for instance, to include the publisher, location,or an ISBN number may vary. The compilation of the complete Guidelines should be referenced as: EAU Guidelines. Edn. presented at the EAU Annual Congress Milan 2021. ISBN 978-94-92671-13-4. If a publisher and/or location is required, include: EAU Guidelines Office, Arnhem, The Netherlands. http://uroweb.org/guidelines/compilations-of-all-guidelines/ References to individual guidelines should be structured in the following way: Contributors’ names. Title of resource. Publication type. ISBN. Publisher and publisher location, year.

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EAU Guidelines on

Renal Cell Carcinoma B. Ljungberg (Chair), L. Albiges, J. Bedke, A. Bex (Vice-chair), U. Capitanio, R.H. Giles (Patient Advocate), M. Hora, T. Klatte T. Lam, L. Marconi, T. Powles, A. Volpe Guidelines Associates: Y. Abu-Ghanem, S. Dabestani, S. Fernández-Pello Montes, F. Hofmann, T. Kuusk, R. Tahbaz

© European Association of Urology 2021

TABLE OF CONTENTS

PAGE

1. INTRODUCTION 1.1 Aims and scope 1.2 Panel composition 1.3 Acknowledgement 1.4 Available publications 1.5 Publication history and summary of changes 1.5.1 Publication history 1.5.2 Summary of changes 2.

METHODS 2.1 Data identification 2.2 Review 2.3 Future goals

6 6 6 6 6 6 6 6 10 10 11 11

3. EPIDEMIOLOGY, AETIOLOGY AND PATHOLOGY 3.1 Epidemiology 3.2 Aetiology 3.2.1 Summary of evidence and recommendation for epidemiology, aetiology and pathology 3.3 Histological diagnosis 3.3.1 Clear-cell RCC 3.3.2 Papillary RCC 3.3.3 Chromophobe RCC 3.4 Other renal tumours 3.4.1 Renal medullary carcinoma 3.4.1.1 Treatment of renal medullary carcinoma 3.4.2 Carcinoma associated with end-stage renal disease; acquired cystic disease associated RCC 3.4.3 Papillary adenoma 3.4.4 Hereditary kidney tumours 3.4.5 Angiomyolipoma 3.4.5.1 Treatment 3.4.6 Renal oncocytoma 3.4.7 Cystic renal tumours 3.5 Summary of evidence and recommendations for the management of other renal tumours 3.6 Recommendations for the management of other renal tumours

14 14 14 15 15 15 17 17 17

4.

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STAGING AND CLASSIFICATION SYSTEMS 4.1 Staging 4.2 Anatomic classification systems

5. DIAGNOSTIC EVALUATION 5.1 Symptoms 5.1.1 Physical examination 5.1.2 Laboratory findings 5.2 Imaging investigations 5.2.1 Presence of enhancement 5.2.2 Computed tomography or magnetic resonance imaging 5.2.3 Other investigations 5.2.4 Radiographic investigations to evaluate RCC metastases 5.2.5 Bosniak classification of renal cystic masses 5.3 Renal tumour biopsy 5.3.1 Indications and rationale 5.3.2 Technique 5.3.3 Diagnostic yield and accuracy 5.3.4 Morbidity 5.4 Summary of evidence and recommendations for the diagnostic assessment of RCC

2

12 12 12 12 12 13 13 13 13 13 13

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6.

PROGNOSTIC FACTORS 6.1 Classification 6.2 Anatomical factors 6.3 Histological factors 6.4 Clinical factors 6.5 Molecular factors 6.6 Prognostic models 6.7 Summary of evidence and recommendations for prognostic factors

7. DISEASE MANAGEMENT 7.1 Treatment of localised RCC 7.1.1 Introduction 7.1.2 Surgical treatment 7.1.2.1 Nephron-sparing surgery versus radical nephrectomy in localised RCC 7.1.2.1.1 T1 RCC 7.1.2.1.2 T2 renal cell carcinoma 7.1.2.2 Associated procedures 7.1.2.2.1 Adrenalectomy 7.1.2.2.2 Lymph node dissection for clinically negative lymph nodes (cN0) 7.1.2.2.3 Embolisation 7.1.2.2.4 Summary of evidence and recommendations for the treatment of localised RCC 7.1.3 Radical and partial nephrectomy techniques 7.1.3.1 Radical nephrectomy techniques 7.1.3.2 Partial nephrectomy techniques 7.1.3.2.1 Open versus laparoscopic approach 7.1.3.2.2 Open versus robotic approach 7.1.3.2.3 Open versus hand-assisted approach 7.1.3.2.4 Open versus laparoscopic versus robotic approaches 7.1.3.2.5 Laparoscopic versus robotic approach 7.1.3.2.6 Surgical volume 7.1.3.3 Positive surgical margins on histopathological specimens 7.1.3.4 Summary of evidence and recommendations for radical and partial nephrectomy techniques 7.1.4 Therapeutic approaches as alternatives to surgery 7.1.4.1 Surgical versus non-surgical treatment 7.1.4.2 Active surveillance and watchful waiting 7.1.4.3 Role of renal tumour biopsy before active surveillance 7.1.4.4 Tumour ablation 7.1.4.4.1 Role of renal mass biopsy 7.1.4.4.2 Cryoablation 7.1.4.4.3 Radiofrequency ablation 7.1.4.4.4 Tumour ablation versus surgery 7.1.4.4.5 Stereotactic ablative radiotherapy 7.1.4.4.6 Other ablative techniques 7.1.4.4.7 Summary of evidence and recommendation for therapeutic approaches as alternative to surgery 7.2 Treatment of locally advanced RCC 7.2.1 Introduction 7.2.2 Role of lymph node invasion in locally advanced RCC 7.2.2.1 Management of clinically negative lymph nodes (cN-) in locally advanced RCC 7.2.2.2 Management of clinically positive lymph nodes (cN+) in locally advanced RCC 7.2.3 Management of locally advanced unresectable RCC 7.2.4 Management of RCC with venous tumour thrombus 7.2.4.1 The evidence base for surgery in patients with venous tumour thrombus

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23 23 23 23 24 24 25 25 27 27 27 27 27 27 28 28 28 29 29 29 30 30 30 30 31 31 31 31 31 31 32 32 32 32 33 33 33 33 34 34 34 35 35 35 35 35 35 35 36 36 36

3

7.2.4.2 The evidence base for different surgical strategies 36 7.2.4.3 Summary of evidence and recommendations for the management of RCC with venous tumour thrombus 36 7.2.5 Neoadjuvant and adjuvant therapy 36 7.2.5.1 Summary of evidence and recommendations for adjuvant therapy 38 7.3 Advanced/metastatic RCC 38 7.3.1 Local therapy of advanced/metastatic RCC 38 7.3.1.1 Cytoreductive nephrectomy 38 7.3.1.1.1 Embolisation of the primary tumour 39 7.3.1.1.2 Summary of evidence and recommendations for local therapy of advanced/metastatic RCC 39 7.3.2 Local therapy of metastases in metastatic RCC 40 7.3.2.1 Complete versus no/incomplete metastasectomy 40 7.3.2.2 Local therapies for RCC bone metastases 40 7.3.2.3 Local therapies for RCC brain metastases 40 7.3.2.4 Embolisation of metastases 41 7.3.2.5 Adjuvant treatment in cM0 patients after metastasectomy 41 7.3.2.6 Summary of evidence and recommendations for local therapy of metastases in metastatic RCC 41 7.4 Systemic therapy for advanced/metastatic RCC 41 7.4.1 Chemotherapy 41 7.4.1.1 Recommendation for systemic therapy in advanced/metastatic RCC 42 7.4.2 Immunotherapy 42 7.4.2.1 IFN-α monotherapy and combined with bevacizumab 42 7.4.2.2 Interleukin-2 42 7.4.2.3 Immune checkpoint blockade 42 7.4.2.3.1 Immuno-oncology monotherapy 42 7.4.2.4 Immunotherapy/combination therapy 42 7.4.2.5 Summary of evidence and recommendations for immunotherapy in metastatic RCC 45 7.4.3 Targeted therapies 46 7.4.3.1 Tyrosine kinase inhibitors 47 7.4.3.1.1 Sorafenib 47 7.4.3.1.2 Sunitinib 47 7.4.3.1.3 Pazopanib 47 7.4.3.1.4 Axitinib 47 7.4.3.1.5 Cabozantinib 47 7.4.3.1.6 Lenvatinib 48 7.4.3.1.7 Tivozanib 48 7.4.4 Monoclonal antibody against circulating VEGF 48 7.4.4.1 Bevacizumab monotherapy and bevacizumab plus IFN-α 48 7.4.5 mTOR inhibitors 48 7.4.5.1 Temsirolimus 48 7.4.5.2 Everolimus 48 7.4.6 Therapeutic strategies 48 7.4.6.1 Therapy for treatment-naïve patients with clear-cell metastatic RCC 48 7.4.6.1.1 Sequencing systemic therapy in clear-cell metastatic RCC 48 7.4.6.2 Non-clear-cell metastatic RCC 49 7.4.7 Summary of evidence and recommendations for targeted therapy in metastatic RCC 50 7.5 Locally recurrent RCC after treatment of localised disease 51 7.5.1 Summary of evidence and recommendation on locally recurrent RCC after treatment of localised disease 52 8. FOLLOW-UP IN RCC 8.1 Introduction 8.2 Which imaging investigations for which patients, and when? 8.3 Summary of evidence and recommendations for surveillance following RN or PN or ablative therapies in RCC 8.4 Research priorities

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9.

REFERENCES

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10.

CONFLICT OF INTEREST

84

11.

CITATION INFORMATION

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5

1.

INTRODUCTION

1.1

Aims and scope

The European Association of Urology (EAU) Renal Cell Cancer (RCC) Guidelines Panel has compiled these clinical guidelines to provide urologists with evidence-based information and recommendations for the management of RCC. It must be emphasised that clinical guidelines present the best evidence available to the experts but following guideline recommendations will not necessarily result in the best outcome. Guidelines can never replace clinical expertise and judgement when making treatment decisions for individual patients, but rather help to focus decisions whilst also taking personal values and preferences/individual circumstances of patients into account. Guidelines are not mandates and do not purport to be a legal standard of care.

1.2

Panel composition

The RCC Guidelines Panel is an international group of clinicians consisting of urological surgeons, oncologists, methodologists, a pathologist and a radiologist, with particular expertise in the field of renal cancer care. Since 2015, the Panel has incorporated a patient advocate to provide a consumer perspective for its guidelines. All experts involved in the production of this document have submitted potential conflict of interest statements, which can be viewed on the EAU website Uroweb: http://uroweb.org/guideline/renalcellcarcinoma/.

1.3

Acknowledgement

The RCC Guidelines Panel is most grateful for the continued methodological and scientific support provided by Prof.Dr. O. Hes (pathologist, Pilzen, Czech Republic) for two sections of this document: Histological diagnosis and Other renal tumours.

1.4

Available publications

A quick reference document (Pocket Guidelines) is available, both in print and as an app for iOS and Android devices, presenting the main findings of the RCC Guidelines. These are abridged versions which may require consultation together with the full text version. Several scientific publications are available, as are a number of translations of all versions of the EAU RCC Guidelines [1]. All documents can be accessed on the EAU website: http://uroweb.org/guideline/renal-cell-carcinoma/.

1.5

Publication history and summary of changes

1.5.1 Publication history The EAU RCC Guidelines were first published in 2000. This 2021 RCC Guidelines document presents a substantial update of the 2020 publication. 1.5.2 Summary of changes All chapters of the 2021 RCC Guidelines have been updated, based on the 2020 version of the Guidelines. References have been added throughout the document. New data have been included in the following sections, resulting in changed recommendations in: Section 5.4 Summary of evidence and recommendations for the diagnostic assessment of RCC Recommendations Strength rating Omit chest CT in patients with incidentally noted cT1a disease due to the low risk of Weak lung metastases in this cohort. Use non-ionising modalities, including MRI and contrast-enhanced ultrasound, for Strong further characterisation of small renal masses, tumour thrombus and differentiation of unclear renal masses, if the results of contrast-enhanced CT are indeterminate.

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Section 6.7 Summary of evidence and recommendations for prognostic factors Summary of evidence In RCC patients, TNM stage, tumour size, grade, and RCC subtype provide important prognostic information. Recommendations Use the WHO/ISUP grading system and classify renal cell carcinoma type. Use prognostic models in localised and metastatic disease. Do not routinely use molecular markers to assess prognosis.

LE 2

Strength rating Strong Strong Strong

7.1.2.2.4 Summary of evidence and recommendations for the treatment of localised RCC Summary of evidence Retrospective studies suggest that oncological outcomes are similar following PN vs. RN in patients with larger (≥ 7 cm) RCC. Post-operative complication rates are higher in PN groups. In patients with localised disease without radiographic evidence of LN metastases, a survival advantage of LND in conjunction with RN is not demonstrated in randomised trials.

LE 3b 2b

Recommendations Offer partial nephrectomy to patients with T2 tumours and a solitary kidney or

Strength rating Weak

chronic kidney disease, if technically feasible. Do not offer an extended lymph node dissection to patients with organ-confined disease.

Weak

7.1.3.4 Summary of evidence and recommendations for radical and partial nephrectomy techniques Summary of evidence Robotic-assisted and laparoscopic PN are associated with shorter length of stay and lower blood loss compared to open PN. Hospital volume in PN might impact on surgical complications, warm ischaemia and surgical margins. Radical nephrectomy after positive surgical margins can result in over-treatment in many cases. Recommendation Intensify follow-up in patients with a positive surgical margin.

LE 2b 3 3

Strength rating Weak

Section 7.1.4.3.7 Summary of evidence and recommendation for therapeutic approaches as alternative to surgery Summary of evidence Low quality studies suggest high disease recurrence rates after radiofrequency ablation of tumours > 3 cm and after cryoablation of tumours > 4 cm. Low quality studies suggest a higher local recurrence rate for thermal ablation therapies compared to PN, but the quality of the data does not allow definitive conclusions. Recommendations Offer active surveillance (AS) or thermal ablation (TA) to frail and/or comorbid patients with small renal masses. Perform a percutaneous renal mass biopsy prior to, and not concomitantly with TA. When TA or AS are offered, discuss with patients about the harms/benefits with regards to oncological outcomes and complications. Do not routinely offer TA for tumours > 3 cm and cryoablation for tumours > 4 cm.

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2021

LE 3 3

Strength rating Weak Strong Strong Weak

7

Section 7.2.4.3 Summary of evidence and recommendations for the management of RCC with venous tumour thrombus Summary of evidence In patients with locally advanced disease, the survival benefit of lymph node (LN) dissection is unproven but LN dissection has significant staging, prognosis and follow-up implications. Recommendations In patients with clinically enlarged lymph nodes (LNs), perform LN dissection to guide staging, prognosis and follow-up. In case of metastatic disease, discuss surgery within the context of a multidisciplinary team.

LE 3

Strength rating Weak Weak

Section 7.2.5.1 Summary of evidence and recommendations for adjuvant therapy Summary of evidence Adjuvant therapy does not improve survival after nephrectomy. In one single RCT, in selected high-risk patients, adjuvant sunitinib improved disease-free survival (DFS) but not overall survival (OS). Adjuvant sorafenib, pazopanib, everolimus, girentuximab or axitinib does not improve DFS or OS after nephrectomy. Adjuvant RCTs are ongoing to evaluate the benefit of adjuvant immunotherapy after nephrectomy in high-risk patients. Recommendations Do not offer adjuvant therapy with sorafenib, pazopanib, everolimus, girentuximab or axitinib. Do not offer adjuvant sunitinib following surgically resected high-risk clear-cell renal cell carcinoma.

LE 1b 1b 1b 1b

Strength rating Strong Weak

Section 7.3.1.1.2 Summary of evidence and recommendations for local therapy of advanced/metastatic RCC Summary of evidence Patients with their primary tumour in place treated with ICI-based combination therapy have better PFS and OS in exploratory subgroup analyses compared to treatment with sunitinib. Recommendation Discuss delayed cytoreductive nephrectomy in patients who derive clinical benefit from systemic therapy.

LE 2b

Strength rating Weak

Section 7.3.2.6 Summary of evidence and recommendations for local therapy of metastases in metastatic RCC Summary of evidence Tyrosine kinase inhibitors treatment after metastasectomy in patients with no evidence of disease did not improve RFS when compared to placebo or observation. Recommendation Do not offer tyrosine kinase inhibitor treatment to mRCC patients after metastasectomy and no evidence of disease.

8

LE 1b

Strength rating Strong

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2021

Section 7.4.2.5 Summary of evidence and recommendations for immunotherapy in metastatic RCC Summary of evidence The combination of pembrolizumab plus axitinib, lenvatinib plus pembrolizumab and nivolumab plus cabozantinib in treatment-naive patients with cc-mRCC across all IMDC risk group demonstrated PFS, OS and ORR benefits compared to sunitinib. Axitinib, cabozantinib or lenvatinib can be continued if immune-related adverse events result in cessation of axitinib plus pembrolizumab, cabozantinib plus nivolumab or lenvatinib plus pembrolizumab. Re-challenge with immunotherapy requires expert support. Nivolumab plus ipilimumab, pembrolizumab plus axitinib, nivolumab plus cabozantinib and lenvatinib plus pembrolizumab should be administered in centres with experience of immune combination therapy and appropriate supportive care within the context of a multidisciplinary team. The combination of nivolumab plus ipilimumab in the IMDC intermediate- and poor-risk population of treatment-naive patients with cc-mRCC leads to superior survival compared to sunitinib while OS was higher in IMDC good-risk patients with sunitinib.

LE 1b

4

4

2b

Recommendations Strength rating Offer pembrolizumab plus axitinib, lenvatinib plus pembrolizumab or nivolumab plus Strong cabozantinib to treatment-naive patients in clear-cell metastatic renal cell carcinoma (cc-mRCC). Administer nivolumab plus ipilimumab, pembrolizumab plus axitinib, lenvatinib plus Weak pembrolizumab and nivolumab plus cabozantinib in centres with experience of immune combination therapy and appropriate supportive care within the context of a multidisciplinary team. Offer axitinib, cabozantinib or lenvatinib as subsequent treatment to patients who experience treatment-limiting immune-related adverse events after treatment with the combination of axitinib plus pembrolizumab, cabozantinib plus nivolumab or lenvatinib plus pembrolizumab.

Weak

Figure 7.1: Updated EAU Guidelines recommendations for the first-line treatment of metastatic ccRCC

Standard of Care

Alternative in patients who can not receive or tolerate immune checkpoint inhibitors

IMDC favourable risk

nivolumab/cabozantinib [1b] pembrolizumab/axitinib [1b] pembrolizumab/lenvatinib [1b]

sunitinib* [1b] pazopanib* [1b]

IMDC intermediate and poor risk

nivolumab/cabozantinib [1b] pembrolizumab/axitinib [1b] pembrolizumab/lenvatinib [1b] nivolumab/ipilimumab [1b]

cabozantinib* [2a] sunitinib*[1b] pazopanib* [1b]

Section 7.4.7 Summary of evidence and recommendations for targeted therapy in metastatic RCC Recommendations Offer nivolumab or cabozantinib for immune checkpoint inhibitor-naive vascular endothelial growth factor receptor (VEGFR)-refractory clear-cell metastatic renal cell carcinoma (cc-mRCC) after one or two lines of therapy. Offer VEGF-tyrosine kinase inhibitors as second-line therapy to patients refractory to nivolumab plus ipilimumab or axitinib plus pembrolizumab, cabozantinib plus nivolumab or lenvatinib plus pembrolizumab.

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Strength rating Strong

Weak

9

Section 8.3 S  ummary of evidence and recommendations for surveillance following RN or PN or ablative therapies in RCC Summary of evidence Functional follow-up after curative treatment for RCC is useful to prevent renal and cardiovascular deterioration. Oncological follow-up can detect local recurrence or metastatic disease while the patient may still be surgically curable. Prognostic models provide stratification of RCC risk of recurrence based on TNM and histological features In competing-risk models, risk of non-RCC-related death exceeds that of RCC recurrence or related death in low-risk patients. Life expectancy estimation is feasible and may support counselling of patients on duration of follow-up.

LE 4 4 3 3 4

Recommendations Strength rating Perform functional follow-up (renal function assessment and prevention of Weak cardiovascular events) both in nephron-sparing (NSS) and radical nephrectomy (RN) patients. Consider curtailing follow-up when the risk of dying from other causes is double that Weak of the recurrence risk of RCC.

2.

METHODS

2.1

Data identification

For the 2021 Guidelines, new and relevant evidence has been identified, collated and appraised through a structured assessment of the literature for the chapters as listed in Table 2.1. A broad and comprehensive scoping search was performed, which was limited to studies representing high certainty of evidence (i.e. systematic reviews with or without meta-analysis, randomised controlled trials (RCTs), and prospective non-randomised comparative studies only for therapeutic interventions, and systematic reviews and prospective studies with well-defined reference standards for diagnostic accuracy studies) published in the English language. In case no higher level data exists for a particular topic, lower level evidence is considered for inclusion. The search was restricted to articles published between April 1st 2019 and June 25th 2020. Databases covered included Medline, EMBASE, and the Cochrane Library. After de-duplication, a total of 1,973 unique records were identified, retrieved and screened for relevance. A total of 106 new references have been included in the 2021 RCC Guidelines publication. A search strategy is published online: https://uroweb.org/guideline/renal-cell-carcinoma/?type=appendices-publications. For each recommendation within the guidelines there is an accompanying online strength rating form, the basis of which is a modified GRADE methodology [2]. Each strength rating form addresses a number of key elements, namely: 1. the overall quality of the evidence which exists for the recommendation; references used in this text are graded according to a classification system modified from the Oxford Centre for Evidence-Based Medicine Levels of Evidence [3]; 2. the magnitude of the effect (individual or combined effects); 3. the certainty of the results (precision, consistency, heterogeneity and other statistical or study-related factors); 4. the balance between desirable and undesirable outcomes; 5. the impact of patient values and preferences on the intervention; 6. the certainty of those patient values and preferences. These key elements are the basis which panels use to define the strength rating of each recommendation. The strength of each recommendation is represented by the words ‘strong’ or ‘weak’ [4]. The strength of each recommendation is determined by the balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including certainty of estimates), and nature and variability of patient values and preferences. The strength rating forms will be available online. 10

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Specific chapters were updated by way of systematic reviews, commissioned and undertaken by the Panel, based on prioritised topics or questions. These reviews were performed using standard Cochrane systematic review methodology: http://www.cochranelibrary.com/about/aboutcochranesystematic-reviews.html. Table 2.1: Description of update and summary of review methodology Chapter 1. Introduction 2. Methods 3. Epidemiology, aetiology and pathology 4. Staging and grading classification systems

5. Diagnostic evaluation

6. Prognosis 7. Treatment (Disease management)

8. F  ollow-up in RCC & Surveillance following radical or partial nephrectomy or ablative therapies

Brief description of review methodology Not applicable. Not applicable. This chapter was updated by a narrative review, based on a structured literature assessment. This chapter was updated by a narrative review, based on a structured literature assessment. Section 3.4.5.1 (Treatment of angiomyolipoma) was updated by means of a systematic review [5]. Section 5.2 (Diagnostic imaging) was revised based on a systematic review [6]. The remainder of the chapter was updated by a structured literature assessment. This chapter was updated by a narrative review, based on a structured literature assessment. Sections 7.1.2 and 7.2.4 (Treatment of localised and locally advanced disease) were revised based on an updated systematic review. Sub-section 7.1.4.3.2 (Cryoablation versus partial nephrectomy) was updated by means of a systematic review [7]. Section 7.4.6.2 (Non-clear-cell metastatic RCC) was updated by means of a systematic review [8]. Some aspects of Section 7.4 (Targeted therapy for metastatic RCC) were updated by way of a Cochrane systematic review [9]. The remainder of the chapter was updated using a structured literature assessment. Systemic therapy for metastatic disease: this section was updated by a systematic review. This chapter was updated by a narrative review, based on a structured literature assessment. The findings of a prospective database set up by the RCC Panel have been included [10, 11].

Additional methodology information can be found in the general Methodology section of this print, and online at the EAU website: http://uroweb.org/guidelines/. A list of Associations endorsing the EAU Guidelines can also be viewed online at the above address.

2.2

Review

All publications ensuing from systematic reviews have been peer reviewed. The 2021 print of the RCC Guidelines was peer-reviewed prior to publication.

2.3

Future goals

For their future updates, the RCC Guideline Panel aims to focus on patient-reported outcomes. The use of clinical quality indicators is an area of interest for the RCC Panel. A number of key quality indicators for this patient group have been selected: • thorax computed tomography (CT) for staging of pulmonary metastasis; • proportion of patients with T1aN0M0 tumours undergoing nephron-sparing surgery (NSS) as first treatment; • the proportion of patients treated within six weeks after diagnosis; • the proportion of patients with metastatic RCC (mRCC) offered systemic therapy; • the proportion of patients who undergo minimally invasive or operative treatment as first treatment who die within 30 days.

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The Panel have set up a database to investigate current practice in follow-up of RCC patients in a number of European centres. Assessing patterns of recurrence and use of imaging techniques are primary outcomes for this project. The results of ongoing and new systematic reviews will be included in the 2022 update of the RCC Guidelines: • What is the best treatment option for ≥ T2 tumours? • Adjuvant targeted therapy for renal cell carcinoma at high risk for recurrence; • Systematic review of prevalence of intraperitoneal recurrences following robotic/laparoscopic partial nephrectomy; • Systematic review of individual, unit and hospital surgical volume for radical and partial nephrectomy and their impact on outcomes; • RECUR database analysis of recurrent disease/follow-up.

3.

EPIDEMIOLOGY, AETIOLOGY AND PATHOLOGY

3.1

Epidemiology

Renal cell carcinoma represents around 3% of all cancers, with the highest incidence occurring in Western countries [12, 13]. In Europe and worldwide the highest incidence rates are found in the Czech Republic and Lithuania [13]. Generally, during the last two decades until recently, there has been an annual increase of about 2% in incidence both worldwide and in Europe leading to approximately 99,200 new RCC cases and 39,100 kidney cancer-related deaths within the European Union in 2018 [12, 13]. In Europe, overall mortality rates for RCC increased until the early 1990s, with rates generally stabilising or declining thereafter [14]. There has been a decrease in mortality since the 1980s in Scandinavian countries and since the early 1990s in France, Germany, Austria, the Netherlands, and Italy. However, in some European countries (Croatia, Estonia, Greece, Ireland, Slovakia), mortality rates still show an upward trend [12, 13]. Renal cell carcinoma is the most common solid lesion within the kidney and accounts for approximately 90% of all kidney malignancies. It comprises different RCC subtypes with specific histopathological and genetic characteristics [15]. There is a 1.5:1 predominance in men over women with a higher incidence in the older population [13, 16].

3.2

Aetiology

Established risk factors include lifestyle factors such as smoking, obesity, and hypertension [13, 16]. In a recent systematic review also diabetes was found to be detrimental [17]. Having a first-degree relative with kidney cancer is also associated with an increased risk of RCC. A number of other factors have been suggested to be associated with higher or lower risk of RCC, including specific dietary habits and occupational exposure to specific carcinogens, but the literature is inconclusive [16]. Moderate alcohol consumption appears to have a protective effect for reasons as yet unknown, while also any physical activity level seems to have a small protective effect [13, 17]. The most effective prophylaxis is to avoid cigarette smoking and reduce obesity [13, 16]. 3.2.1

Summary of evidence and recommendation for epidemiology, aetiology and pathology

Summary of evidence Several verified risk factors have been identified including smoking, obesity and hypertension. These are considered definite risk factors for RCC.

Recommendation Increase physical activity, eliminate cigarette smoking and in obese patients reduce weight are the primary preventative measures to decrease risk of RCC.

3.3

LE 2a

Strength rating Strong

Histological diagnosis

Renal cell carcinomas comprise a broad spectrum of histopathological entities described in the 2016 World Health Organization (WHO) classification [15]. There are three main RCC types: clear cell (ccRCC), papillary (pRCC type I and II) and chromophobe (chRCC). The RCC type classification has been confirmed by

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cytogenetic and genetic analyses [15, 18] (LE: 2b). Collecting duct carcinoma and other rare renal tumours are discussed in Section 3.3. Histological diagnosis includes, besides RCC type; evaluation of nuclear grade, sarcomatoid features, vascular invasion, tumour necrosis, and invasion of the collecting system and peri-renal fat, pT, or even pN categories. The four-tiered WHO/ISUP (International Society of Urological Pathology) grading system has replaced the Fuhrman grading system [15]. 3.3.1 Clear-cell RCC Overall, clear-cell RCC (ccRCC) is well circumscribed and a capsule is usually absent. The cut surface is golden-yellow, often with haemorrhage and necrosis. Loss of chromosome 3p and mutation of the von HippelLindau (VHL) gene at chromosome 3p25 are frequently found. The loss of von Hippel-Lindau protein function contributes to tumour initiation, progression, and metastases. The 3p locus harbours at least four additional cRCC tumour supressor genes (UTX, JARID1C, SETD2, PBRM1) [18]. In general, ccRCC has a worse prognosis compared to pRCC and chRCC, but this difference disappears after adjustment for stage and grade [19, 20]. For details about prognosis, see Section 6.3 - Histological factors. 3.3.2 Papillary RCC Papillary RCC is the second most commonly encountered morphotype of RCC. Papillary RCC has traditionally been subdivided into two types [15]. Type I and II pRCC, which were shown to be clinically and biologically distinct; pRCC type I is associated with activating germline mutations of MET and pRCC type II is associated with activation of the NRF2-ARE pathway and at least three subtypes [21]. Type II pRCC presents a heterogenous group of tumours and future substratification is expected, e.g. oncocytic pRCC [15]. A typical histology of pRCC type I (narrow papillae without any binding, and only microcapillaries in papillae) explains its typical clinical signs. Narrow papillae without any binding and a tough pseudocapsule explain the ideal rounded shape (Pascal’s law) and fragility (specimens have a “minced meat” structure). Tumour growth causes necrotisation of papillae, which is a source of hyperosmotic proteins that cause subsequent “growth” of the tumour, fluid inside the tumour, and only a serpiginous, contrast-enhancing margin. Stagnation in the microcapillaries explain the minimal post-contrast attenuation on CT. Papillary RCC type 1 can imitate a pathologically changed cyst (Bosniak IIF or III). The typical signs of pRCC type 1 are as follows: an ochre colour, more frequently exophytic, extrarenal growth, low grade, and low malignant potential; over 75% of these tumours can be treated by NSS surgery. A substantial risk of renal tumour biopsy tract seeding exists (12.5%), probably due to the fragility of the tumour papillae [22]. Papillary RCC type I is more common and generally considered to have a better prognosis than pRCC type II [15, 20, 23]. 3.3.3 Chromophobe RCC Overall, chRCC is a pale tan, relatively homogenous and tough, well-demarcated mass without a capsule. Chromophobe RCC cannot be graded by the Fuhrman grading system because of its innate nuclear atypia. An alternative grading system has been proposed, but has yet to be validated [15]. Loss of chromosomes Y, 1, 2, 6, 10, 13, 17 and 21 are typical genetic changes [15]. The prognosis is relatively good, with high 5-year recurrence-free survival (RFS), and 10-year CSS [24]. The new WHO/ISUP grading system merges former entity ‘hybrid oncocytic chromophobe tumour’ with chRCC.

3.4

Other renal tumours

Other renal tumours constitute the remaining renal cortical tumours. These include a variety of uncommon, sporadic, and familial carcinomas, some only recently described, as well as a group of unclassified carcinomas. A summary of these tumours is provided in Table 3.1, but some clinically relevant tumours and extremely rare entities are mentioned below. 3.4.1 Renal medullary carcinoma Renal medullary carcinoma (RMC) is a very rare tumour, comprising < 0.5% of all RCCs [25], predominantly diagnosed in young adults (median age 28 years) with sickle haemoglobinopathies (including sickle cell trait). It is mainly centrally located with ill-defined borders. Renal medullary carcinoma is one of the most aggressive RCCs [26, 27] and most patients (~67%) will present with metastatic disease [26, 28]. Even patients who present with seemingly localised disease may develop macrometastases shortly thereafter, often within a few weeks. 3.4.1.1 Treatment of renal medullary carcinoma Despite treatment, median OS is 13 months in the most recent series [26]. Due to the infiltrative nature and medullary epicentre of RMC, radical nephrectomy (RN) is favoured over PN even in very early-stage disease. Retrospective data indicate that nephrectomy in localised disease results in superior OS (16.4 vs. 7 months)

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compared with systemic chemotherapy alone, but longer survival was noted in patients who achieved an objective response to first-line chemotherapy. [26, 29]. There is currently no established role for distant metastasectomy or nephrectomy in the presence of metastases. Palliative radiation therapy is an option and may achieve regression in the targeted areas but it will not prevent progression outside the radiation field [30, 31]. Renal medullary carcinoma is refractory to monotherapies with targeted anti-angiogenic regimens including tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors [26, 32]. The mainstay systemic treatments for RMC are cytotoxic combination regimens which produce partial or complete responses in ~29% of patients [32]. There are no prospective comparisons between different chemotherapy regimens but most published series used various combinations of platinum agents, taxanes, gemcitabine, and/or anthracyclines [26, 27]. High-doseintensity combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) has also shown efficacy against RMC [33] although a retrospective comparison did not show superiority of MVAC over cisplatin, paclitaxel, and gemcitabine [27]. Single-agent anti-PD-1 (monoclonal antibodies against programmed death-1) immune checkpoint therapy has produced responses in a few case reports, although, as yet, insufficient data are available to determine the response rate to this approach [30, 31]. Whenever possible, patients should be enrolled in clinical trials of novel therapeutic approaches, particularly after failing first-line cytotoxic chemotherapy. 3.4.2 Carcinoma associated with end-stage renal disease; acquired cystic disease-associated RCC Cystic degenerative changes (acquired cystic kidney disease [ACKD]) and a higher incidence of RCC, are typical features of end-stage renal disease (ESRD). Renal cell carcinomas of native end-stage kidneys are found in approximately 4% of patients. Their lifetime risk of developing RCCs is at least ten times higher than in the general population. Compared with sporadic RCCs, RCCs associated with ESRD are generally multicentric and bilateral, found in younger patients (mostly male), and are less aggressive. Whether the relatively indolent outcome of tumours in ESRD is due to the mode of diagnosis or a specific ACKD-related molecular pathway still has to be determined. Although the histological spectrum of ESRD tumours is similar to that of sporadic RCC; pRCC occur relatively more frequently [34, 35]. A specific subtype of RCC occurring only in end-stage kidneys has been described as Acquired Cystic Disease-associated RCC (ACD-RCC) with indolent clinical behaviour, likely due to early detection in patients with ESRD on periodic follow-up [15, 18, 36]. 3.4.3 Papillary adenoma These tumours have a papillary or tubular architecture of low nuclear grade and may be up to 15 mm in diameter, or smaller [37], according to the WHO 2016 classification [15]. 3.4.4 Hereditary kidney tumours Five to eight percent of RCCs are hereditary; to date there are ten hereditary RCC syndromes associated with specific germline mutations, RCC histology, and comorbidities. Hereditary RCC syndromes are often suggested by family history, age of onset and presence of other lesions typical for the respective syndromes. Median age for hereditary RCC is 37 years; 70% of hereditary RCC tumours are found in the lowest decile (46 years old) of all RCC tumours [38]. Hereditary kidney tumours are found in the following entities: VHL syndrome, hereditary pRCC, Birt-Hogg-Dube syndrome, hereditary leiomyomatosis and RCC (HLRCC), tuberous sclerosis, germline succinate dehydrogenase (SDH) mutation, non-polyposis colorectal cancer syndrome, hyperparathyroidism-jaw tumour syndrome, phosphatase and tensin homolog (PTEN) hamartoma syndrome (PHTS), constitutional chromosome 3 translocation, and familial non-syndromic ccRCC. Renal medullary carcinoma can be included because of its association with hereditary haemoglobinopathies [37, 39-41]. Patients with hereditary kidney cancer syndromes may require repeated surgical intervention [42, 43]. In most hereditary RCCs nephron-sparing approaches are recommended. The exceptions are HLRCC and SDH syndromes for which immediate surgical intervention is recommended due to the aggressive nature of this lesion. For other hereditary syndromes such as VHL, surveillance is recommended until the largest tumour reaches 3 cm in diameter, to reduce interventions [44]. Active surveillance (AS) for VHL, BDH and HPRCC should, in individual patients, follow the growth kinetics, size and location of the tumours, rather than apply a standardised follow-up interval. Regular screening for both renal and extra-renal lesions should follow international guidelines for these syndromes. Multidisciplinary and co-ordinated care should be offered, where appropriate [45]. Although not hereditary, somatic fusion translocations of TFE3 and TFEB may affect 15% of patients with RCC younger than 45 years and 20-45% of children and young adults diagnosed with RCC [46]. A recent phase II trial demonstrated clinical activity of an oral HIF-2α (hypoxia-inducible factor) inhibitor MK-6482 in VHL patients. In VHL-associated RCC the objective response rate (ORR) was 28%

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and stable disease rate was observed in 71% of 61 evaluated patients with a median decline of the linear growth rate by -6.4 mm (range 23.3–4.5) per year. Eighty seven per cent of patients showed a decrease from baseline in target lesions as evaluated by independent review, which, despite a follow-up of 36 weeks only, are promising but, as yet, unvalidated results [47]. Genetic counselling is suggested for younger patients, in case of bilateral and multiple tumours, a past family history of RCC and uncommon morphology. 3.4.5 Angiomyolipoma Angiomyolipoma (AML) is a benign mesenchymal tumour, which can occur sporadically or as part of tuberous sclerosis complex [48]. Overall prevalence is 0.44%, with 0.6% in female and 0.3% in male populations. Only 5% of these patients present with multiple AMLs [49]. Angiomyolipoma belongs to a family of so-called PEComas (perivascular epithelioid cell tumours), characterised by the proliferation of perivascular epithelioid cells. Some PEComas can behave aggressively and can even produce distant metastases. Classic AMLs are completely benign [15, 37, 50]. Ultrasound (US), CT, and magnetic resonance imaging (MRI) often lead to the diagnosis of AMLs due to the presence of adipose tissue, however in fat poor AML, diagnostic imaging cannot reliably identify these lesions. Percutaneous biopsy is rarely useful. Renal tumours that cannot be clearly identified as benign during the initial diagnostic work-up should be treated according to the recommendations provided for the treatment of RCC in these Guidelines. In tuberous sclerosis, AML can be found in enlarged lymph nodes (LNs), which does not represent metastatic spread but a multicentric spread of AMLs. In rare cases, an extension of a non-malignant thrombus into the renal vein or inferior vena cava can be found, associated with an angiotrophic-type growth of AML. Epithelioid AML, a very rare variant of AML, consists of at least 80% epithelioid cells [37, 50]. Epithelioid AMLs are potentially malignant with a highly variable proportion of cases with aggressive behaviour [51]. Criteria to predict the biological behaviour in epithelioid AML were proposed by the WHO 2016 [37, 50]. Angiomyolipoma, in general, has a slow and consistent growth rate, and minimal morbidity [5]. In some cases, larger AMLs can cause local pain. The main complication of AMLs is spontaneous bleeding in the retroperitoneum or into the collecting system, which can be life threatening. Bleeding is caused by spontaneous rupture of the tumour. Little is known about the risk factors for bleeding, but it is believed to increase with tumour size and may be related to the angiogenic component of the tumour that includes irregular blood vessels [5]. The major risk factors for bleeding are tumour size, grade of the angiogenic component, and the presence of tuberous sclerosis [52, 53]. 3.4.5.1 Treatment Active surveillance is the most appropriate option for most AMLs (48%). In a group of patients on AS, only 11% of AMLs showed growth, and spontaneous bleeding was reported in 2%, resulting in active treatment in 5% of patients [5, 54] (LE: 3). The association between AML size and the risk of bleeding remains unclear and the traditionally used 4-cm cut-off should not per se trigger active treatment [5]. When surgery is indicated, NSS is the preferred option, if technically feasible. Main disadvantages of less invasive selective arterial embolisation (SAE) are more recurrences and a need for secondary treatment (0.85% for surgery vs. 31% for SAE). For thermal ablation only limited data are available, and this option is used less frequently [5]. Active treatment (SAE, surgery or ablation) should be instigated in case of persistent pain, ruptured AML (acute or repeated bleeding) or in case of a very large AML. Specific patient circumstances may influence the choice to offer active treatment; such as patients at high risk of abdominal trauma, females of childbearing age or patients in whom follow-up or access to emergency care may be inadequate. Selective arterial embolisation is an option in case of life-threatening AML bleeding. In patients diagnosed with tuberous sclerosis, size reduction of often bilateral AMLs can be induced by inhibiting the mTOR pathway using everolimus, as demonstrated in RCTs [55, 56]. In a small phase II trial (n = 20), efficacy of everolimus was demonstrated in sporadic AML as well. A 25% or greater reduction in tumour volume at 4 and 6 months was demonstrated in 55.6% and 71.4% of patients, respectively. Twenty per cent of patients were withdrawn due to toxicities and 40% self-withdrew from the study due to side effects [57]. 3.4.6 Renal oncocytoma Oncocytoma is a benign tumour representing 3–7% of all solid renal tumours and its incidence increases to 18% when tumours < 4 cm are considered [15, 54]. The diagnostic accuracy of imaging modalities (CT, MRI) in renal oncocytoma is limited and histopathology remains the only reliable diagnostic modality [15, 54]. Standard treatment for renal oncocytoma is similar to that of other renal tumours; surgical excision by partial- or RN with subsequent histopathological verification. However, due to the inability of modern imaging techniques to differentiate benign from malignant renal masses, there is a renewed interest in renal mass biopsy (RMB) prior to surgical intervention. Accuracy of the biopsy and management of advanced/progressing oncocytomas

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need to be considered in this context since oncocytic renal neoplasms diagnosed by RMB at histological examination after surgery showed oncocytoma in only 64.6% of cases. The remainder of the tumours were mainly chRCC (18.7% including 6.3% hybrid oncocytic/chromophobe tumours which have now been grouped histologically with chRCC) [15], other RCCs (12.5%), and other benign lesions (4.2%) [58]. The majority of oncocytomas slowly progress in size with an annual growth rate < 14 mm [59-61]. Preliminary data show that AS may be a safe option to manage oncocytoma in appropriately selected patients. Potential triggers to change management of patients on AS are not well defined [62]. Table 3.1: Other renal cortical tumours, and recommendations for treatment (strength rating: weak) [15] Entity Sarcomatoid variants of RCC

Clinical relevant notes Sign of high-grade transformation without being a distinct histological entity.

Malignant potential High

Multilocular cystic renal neoplasm of low malignant potential Carcinoma of the collecting ducts of Bellini

Formerly multilocular cystic RCC

Benign

Rare, often presenting at an advanced stage (N+ 44% and M1, 33% at diagnosis). The hazard ratio (HR) for CSS in comparison with ccRCC is 4.49 [20]. Very rare. Mainly young black men with sickle cell trait.

High, very aggressive. Median survival is 30 months [64].

Surgery. Response to targeted therapies is poor [65].

High, very aggressive, median survival is five months [64].

Intermediate

Surgery. Different chemotherapy regimens, radiosensitive. Surgery. Vascular endothelial growth factor (VEGF)-targeted therapy. Surgery, NSS. VEGFtargeted therapy. Surgery, NSS.

Low

Surgery, NSS.

Low

Surgery, NSS.

High

Low (90% indolent)

Surgery. No data about treatment of metastatic disease. Imaging screening is recommended [67]. Surgery, NSS.

Variable

Surgery, NSS.

Renal medullary carcinoma

Translocation RCC (TRCC) Xp11.2

High Rare, mainly younger patients < 40, more common in females. Less commonly, TFEB located on the short arm of chromosome 6 (6p21) [66]. Low/intermediate

Translocation RCC t(6;11) Mucinous tubular and Tumour is associated with the spindle cell carcinoma loop of Henle. Acquired cystic diseaseassociated RCC Clear-cell papillary RCC Also reported as renal angiomyomatous tumour (RAT). Rare, germline mutation of the Hereditary fumarate hydratase gene [15]. leiomyomatosis and 21% lifetime risk of RCC [67]. RCC-associated RCC

Tubulocystic RCC Succinate dehydrogenasedeficient RCC Metanephric tumours

Mainly men, imaging can show Bosniak III or IV. Rare.

Benign Divided into metanephric adenoma, adenofibroma, and metanephric stromal tumours. Low/benign Cystic nephroma/Mixed The term renal epithelial and stromal tumours (REST) is used epithelial and stromal as well. Imaging – Bosniak type tumour III or II/IV.

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Treatment Surgery. Nivolumab and ipilimumab. Sunitinib, gemcitabine plus doxorubicin is also an option [63]. Nephron-sparing surgery (NSS).

Surgery, NSS.

Surgery, NSS.

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Oncocytoma

Renal cysts

Benign 3-7% of all renal tumours. Imaging characteristics alone are unreliable when differentiating between oncocytoma and RCC. Histopathological diagnosis remains the reference standard. Malignant or benign Simple cysts are frequently occurring, while occurring septa, calcifications and solid components require follow-up and/or management.

Observation (when histologically confirmed). NSS. See Section 3.4.6.

Treatment or followup recommendation based on Bosniak classification. See Table 5.1

3.4.7 Cystic renal tumours Cystic renal lesions are classified according to the Bosniak classification (see Section 5.2.5). Bosniak I and II cysts are benign lesions which do not require follow up [68]. Bosniak IV cysts are mostly malignant tumours with pseudocystic changes only. Bosniak IIF and III cysts remain challenging for clinicians. The differentiation of benign and malignant tumour in categories IIF/III is based on imaging, mostly CT, with an increasing role of MRI and contrast enhanced ultrasound (CEUS). Computed tomography shows poor sensitivity (36%) and specificity (76%; κ [kappa coefficient] = 0.11) compared with 71% sensitivity and 91% specificity (κ = 0.64) for MRI and 100% sensitivity and 97% specificity for CEUS (κ = 0.95) [69]. Surgical and radiological cohorts pooled estimates show a prevalence of malignancy of 0.51 (0.44–0.58) in Bosniak III and 0.89 (0.83–0.92) in Bosniak IV cysts, respectively. In a systematic review, less than 1% of stable Bosniak IIF cysts showed malignancy during follow-up. Twelve percent of Bosniak IIF cysts had to be reclassified to Bosniak III/IV during radiological follow-up, with 85% of these showing malignancy, which is comparable to the malignancy rates of Bosniak IV cysts [68]. The updated Bosniak classification strengthens the classification and includes also MRI diagnostic criteria [70]. The most common histological type for Bosniak III cysts is ccRCC with pseudocystic changes and low malignant potential [71, 72]; multilocular cystic renal neoplasm of low malignant potential ([MCRNLMP], formerly mcRCC (see Section 3.2 and Table 3.1); pRCC type I (very low malignant potential); benign multilocular cyst; benign group of renal epithelial and stromal tumours (REST); and other rare entities. Surgery in Bosniak III cysts will result in over-treatment in 49% of the tumours which are lesions with a low malignant potential. In view of the excellent outcome of these patients in general, a surveillance approach is an alternative to surgical treatment [68, 70, 73, 74].

3.5

Summary of evidence and recommendations for the management of other renal tumours

Summary of evidence A variety of renal tumours exist of which approximately 15% are benign. Recent histological work up of Bosniak III cysts shows low risk of malignant potential.

3.6

LE 1b 2

Recommendations for the management of other renal tumours

Recommendations Manage Bosniak type III cysts the same as localised RCC, or offer active surveillance. Manage Bosniak type IV cysts the same as localised RCC. Treat angiomyolipoma (AML) with selective arterial embolisation or nephron-sparing surgery, in: • large tumours (a recommended threshold of intervention does not exist); • females of childbearing age; • patients in whom follow-up or access to emergency care may be inadequate; • persistent pain or acute or repeated bleeding episodes. Offer systemic therapy to patients in need of therapy with surgically unresectable AMLs not amendable to embolisation or surgery. Offer active surveillance to patients with biopsy-proven oncocytomas, as an acceptable alternative to surgery or ablation. Offer radical nephrectomy to patients with localised renal medullary carcinoma. Base systemic therapy for renal medullary carcinoma on chemotherapy regimens containing cisplatinum such as cisplatin plus gemcitabine.

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Strength rating Weak Strong Weak

Weak Weak Weak Weak

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4.

STAGING AND CLASSIFICATION SYSTEMS

4.1

Staging

The Tumour Node Metastasis (TNM) classification system is recommended for clinical and scientific use [75], but requires continuous re-assessment [15, 76]. A supplement was published in 2012, and the latter’s prognostic value was confirmed in single and multi-institution studies [77, 78]. Tumour size, venous invasion, renal capsular invasion, adrenal involvement, and LN and distant metastasis are included in the TNM classification system (Table 4.1). However, some uncertainties remain: • The sub-classification of T1 tumours using a cut-off of 4 cm might not be optimal in NSS for localised cancer. • The value of size stratification of T2 tumours has been questioned [79]. • Renal sinus fat invasion might carry a worse prognosis than perinephric fat invasion, but, is nevertheless included in the same pT3a stage group [80-82] (LE: 3). • Sub T-stages (pT2b, pT3a, pT3c and pT4) may overlap [78]. • For adequate M staging, accurate pre-operative imaging (chest and abdominal CT) should be performed [83, 84] (LE: 4). Table 4.1: 2017 TNM classification system [75] T - Primary tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour Tumour < 7 cm or less in greatest dimension, limited to the kidney T1 Tumour < 4 cm or less T1a Tumour > 4 cm but < 7 cm T1b T2 Tumour > 7 cm in greatest dimension, limited to the kidney Tumour > 7 cm but < 10 cm T2a T2b Tumours > 10 cm, limited to the kidney T3 Tumour extends into major veins or perinephric tissues but not into the ipsilateral adrenal gland and not beyond Gerota fascia T3a Tumour extends into the renal vein or its segmental branches, or invades the pelvicalyceal system or invades perirenal and/or renal sinus fat, but not beyond Gerota fascia* T3b Tumour grossly extends into the vena cava below diaphragm T3c Tumour grossly extends into vena cava above the diaphragm or invades the wall of the vena cava T4 Tumour invades beyond Gerota fascia (including contiguous extension into the ipsilateral adrenal gland) N - Regional Lymph Nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in regional lymph node(s) M - Distant Metastasis M0 No distant metastasis M1 Distant metastasis pTNM stage grouping Stage I T1 N0 M0 Stage II T2 N0 M0 Stage III T3 N0 M0 T1, T2, T3 N1 M0 Stage IV T4 Any N M0 Any T Any N M1 A help desk for specific questions about TNM classification is available at http://www.uicc.org/tnm. *Adapted based on the American Joint Committee on Cancer (AJCC), 8th Edn. 2017 [85].

4.2

Anatomic classification systems

Objective anatomic classification systems, such as the Preoperative Aspects and Dimensions Used for an Anatomical (PADUA) classification system, the R.E.N.A.L. nephrometry score, the C-index, an Arterial Based Complexity (ABC) Scoring System and Zonal NePhRO scoring system, have been proposed to standardise the description of renal tumours [86-88]. These systems include assessment of tumour size, exophytic/endophytic properties, proximity to the collecting system and renal sinus, and anterior/posterior or lower/upper pole location.

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The use of such a system is helpful as it allows objective prediction of potential morbidity of NSS and tumour ablation techniques. These tools provide information for treatment planning, patient counselling, and comparison of PN and tumour ablation series. However, when selecting the most optimal treatment option, anatomic scores must be considered together with patient features and surgeon experience.

5.

DIAGNOSTIC EVALUATION

5.1

Symptoms

Many renal masses remain asymptomatic until the late disease stages. More than 50% of RCCs are detected incidentally by non-invasive imaging investigating various non-specific symptoms and other abdominal diseases [78, 89] (LE: 3). The classic triad of flank pain, visible haematuria, and palpable abdominal mass is rare (6–10%) and correlates with aggressive histology and advanced disease [90, 91] (LE: 3). Paraneoplastic syndromes are found in approximately 30% of patients with symptomatic RCCs [92] (LE: 4). Some symptomatic patients present with symptoms caused by metastatic disease, such as bone pain or persistent cough [93] (LE: 3). 5.1.1 Physical examination Physical examination has a limited role in RCC diagnosis. However, the following findings should prompt radiological examinations: • palpable abdominal mass; • palpable cervical lymphadenopathy; • non-reducing varicocele and bilateral lower extremity oedema, which suggests venous involvement. 5.1.2 Laboratory findings Commonly assessed laboratory parameters are serum creatinine, glomerular filtration rate (GFR), complete cell blood count, erythrocyte sedimentation rate, liver function study, alkaline phosphatase, lactate dehydrogenase (LDH), serum corrected calcium [94], coagulation study, and urinalysis (LE: 4). For central renal masses abutting or invading the collecting system, urinary cytology and possibly endoscopic assessment should be considered in order to exclude urothelial cancer (LE: 4). Split renal function should be estimated using renal scintigraphy in the following situations [95, 96] (LE: 2b): • when renal function is compromised, as indicated by increased serum creatinine or significantly decreased GFR; • when renal function is clinically important; e.g., in patients with a solitary kidney or multiple or bilateral tumours. Renal scintigraphy is an additional diagnostic option in patients at risk of future renal impairment due to comorbid disorders.

5.2

Imaging investigations

Most renal tumours are diagnosed by abdominal US or CT performed for other medical reasons [89] (LE: 3). Renal masses are classified as solid or cystic based on imaging findings. 5.2.1 Presence of enhancement With solid renal masses, the most important criterion for differentiating malignant lesions is the presence of enhancement [97] (LE: 3). Traditionally, US, CT and MRI are used for detecting and characterising renal masses. Most renal masses are diagnosed accurately by imaging alone. 5.2.2 Computed tomography or magnetic resonance imaging Computed tomography or MRI are used to characterise renal masses. Imaging must be performed unenhanced, in an early arterial phase, and in a parchymal phase with intravenous contrast material to demonstrate enhancement. In CT imaging, enhancement in renal masses is determined by comparing Hounsfield units (HUs) before, and after, contrast administration. A change of fifteen HU, or more, in the solid tumour parts demonstrates enhancement and thus vital tumour parts [98] (LE: 3). Computed tomography or MRI allows accurate diagnosis of RCC, but cannot reliably distinguish oncocytoma and fat-free AML from

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malignant renal neoplasms [99-102] (LE: 3). Abdominal CT provides information on [103]: • function and morphology of the contralateral kidney [104] (LE: 3); • primary tumour extension; • venous involvement; • enlargement of locoregional LNs; • condition of the adrenal glands and other solid organs (LE: 3). Abdominal contrast-enhanced CT angiography is useful in selected cases when detailed information on the renal vascular supply is needed [105, 106]. If the results of CT are indeterminate, CEUS is a valuable alternative to further characterise renal lesions [6, 107-109] (LE: 1b). Magnetic resonance imaging may provide additional information on venous involvement if the extent of an inferior vena cava (IVC) tumour thrombus is poorly defined on CT [110-113] (LE: 3). In MRI, especially highresolution T2 weighted images provide a superior delineation of the uppermost tumour thrombus, as the inflow of the enhanced blood may be reduced due to extensive occlusive tumour thrombus growth in the inferior vena cava. The T2 weighted images with its intrinsic contrast allows a good delineation [113]. Magnetic resonance imaging is indicated in patients who are allergic to intravenous CT contrast medium and in pregnancy without renal failure [113, 114] (LE: 3). Magnetic resonance imaging allows the evaluation of a dynamic enhancement without radiation exposure. Advanced MRI techniques such as diffusion-weighted (DWI) and perfusion-weighted imaging are being explored for renal mass assessment [115]. Recently, the use of multiparametric MRI (mpMRI) to diagnose ccRCC via a clear cell likelihood score (ccLS) in small renal masses was reported [116]. The ccLS is a 5-tier classification that denotes the likelihood of a mass representing ccRCC, ranging from ‘very unlikely’ to ‘very likely’. The authors prospectively validated the diagnostic performance of ccLS in 57 patients with cT1a tumours and found a high diagnostic accuracy. The diagnostic performance of mpMRI-based ccLS was further validated in a larger retrospective cohort (n = 434) across all tumour sizes and stages [117], and ccLS was found to be an independent prognostic factor for identifying ccRCC. The system is promising and deserves further validation. For the diagnosis of complex renal cysts (Bosniak IIF-III) MRI may be preferable. The accuracy of CT is limited in these cases, with poor sensitivity (36%) and specificity (76%; κ = 0.11); MRI, due to a higher sensitivity for enhancement, showed a 71% sensitivity and 91% specificity (κ = 0.64). Contrast-enhanced US showed high sensitivity (100%) and specificity (97%), with a negative predictive value of 100% (κ = 0.95) [69]. In younger patients who are worried about the radiation exposure of frequent CT scans, MRI may be offered as alternative although only limited data exist correlating diagnostic radiation exposure to the development of secondary cancers [118]. 5.2.3 Other investigations Renal arteriography and inferior venacavography have a limited role in the work-up of selected RCC patients (LE: 3). In patients with any sign of impaired renal function, an isotope renogram and total renal function evaluation should be considered to optimise treatment decision-making [95, 96] (LE: 2a). Positron-emission tomography (PET) is not recommended [6, 119] (LE: 1b). 5.2.4 Radiographic investigations to evaluate RCC metastases Chest CT is accurate for chest staging [83, 84, 120-122] (LE: 3). Use of nomograms to calculate risk of lung metastases have been proposed based on tumour size, clinical stage and presence of systemic symptoms [123, 124]. These are based on large, retrospective datasets, and suggest that chest CT may be omitted in patients with cT1a and cN0, and without systemic symptoms, anaemia or thrombocythemia, due to the low incidence of lung metastases (< 1%) in this group of patients. There is a consensus that most bone metastases are symptomatic at diagnosis; thus, routine bone imaging is not generally indicated [120, 125, 126] (LE: 3). However, bone scan, brain CT, or MRI may be used in the presence of specific clinical or laboratory signs and symptoms [125, 127, 128] (LE: 3). A recent prospective comparative blinded study involving 92 consecutive mRCC patients treated with first-line VEGFR-TKI (median follow-up 35 months) found that whole-body DWI/ MRI detected a statistically significant higher number of bony metastases compared with conventional thoraco-abdomino-pelvic contrast-enhanced CT, with higher number of metastases being an independent prognostic factor for progression-free survival (PFS) and OS [129]. 5.2.5 Bosniak classification of renal cystic masses This system classifies renal cysts into five categories, based on CT imaging appearance, to predict malignancy risk [130, 131] (LE: 3), and also advocates treatment for each category (Table 5.1). A new updated Bosniak classification has been proposed that strengthens the classification and includes MRI diagnostic criteria

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[70]; however, it requires further validation. The management of cystic renal tumours is also discussed in Section 3.4.7. Table 5.1: Bosniak classification of renal cysts [130] Bosniak Features category I Simple benign cyst with a hairline-thin wall without septa, calcification, or solid components. Same density as water and does not enhance with contrast medium. II Benign cyst that may contain a few hairline-thin septa. Fine calcification may be present in the wall or septa. Uniformly high-attenuation lesions < 3 cm in size, with sharp margins without enhancement. IIF These may contain more hairline-thin septa. Minimal enhancement of a hairline-thin septum or wall. Minimal thickening of the septa or wall. The cyst may contain calcification, which may be nodular and thick, with no contrast enhancement. No enhancing soft-tissue elements. This category also includes totally intra-renal, non-enhancing, high attenuation renal lesions ≥ 3 cm. Generally well-marginated. III These are indeterminate cystic masses with thickened irregular walls or septa with enhancement.

IV

5.3

Clearly malignant containing enhancing soft-tissue components.

Work-up Benign

Benign

Follow-up, up to five years. Some are malignant.

Surgery or active surveillance – see Chapter 7. Over 50% are malignant. Surgery. Most are malignant.

Renal tumour biopsy

5.3.1 Indications and rationale Percutaneous renal tumour biopsy can reveal histology of radiologically indeterminate renal masses and can be considered in patients who are candidates for AS of small masses, to obtain histology before ablative treatments, and to select the most suitable medical and surgical treatment strategy in the setting of metastatic disease [132-137] (LE: 3). A multicentre study assessing 542 surgically removed small renal masses showed that the likelihood of benign findings at pathology is significantly lower in centres where biopsies are performed (5% vs. 16%), suggesting that biopsies can reduce surgery for benign tumours and the potential for short-term and long-term morbidity associated with these procedures [138]. Renal biopsy is not indicated for comorbid and frail patients who can be considered only for conservative management (watchful waiting) regardless of biopsy results. Due to the high diagnostic accuracy of abdominal imaging, renal tumour biopsy is not necessary in patients with a contrast-enhancing renal mass for whom surgery is planned (LE: 4). Core biopsies of cystic renal masses have a lower diagnostic yield and accuracy and are not recommended alone, unless areas with a solid pattern are present (Bosniak IV cysts) [132, 135, 139] (LE: 2b/3). 5.3.2 Technique Percutaneous sampling can be performed under local anaesthesia with needle core biopsy and/or fine needle aspiration (FNA). Biopsies can be performed under US or CT guidance, with a similar diagnostic yield [135, 140] (LE: 2b). Eighteen-gauge needles are ideal for core biopsies, as they result in low morbidity and provide sufficient tissue for diagnosis [132, 136, 141] (LE: 2b). A coaxial technique allowing multiple biopsies through a coaxial cannula should always be used to avoid potential tumour seeding [132, 136] (LE: 3). Core biopsies are preferred for the characterisation of solid renal masses while a combination with FNA can provide complimentary results and improve accuracy for complex cystic lesions [139, 142, 143] (LE: 2a). A systematic review and meta-analysis of the diagnostic performance and complications of renal tumour biopsy was performed by the Panel, including 57 publications and a total of 5,228 patients. Needle core biopsies were found to have better accuracy for the diagnosis of malignancy compared with FNA [139]. Other studies showed that solid pattern, larger tumour size and exophytic location are predictors of a diagnostic core biopsy [132, 135, 140] (LE: 2b).

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5.3.3 Diagnostic yield and accuracy In experienced centres, core biopsies have a high diagnostic yield, specificity, and sensitivity for the diagnosis of malignancy. The above-mentioned meta-analysis showed that sensitivity and specificity of diagnostic core biopsies for the diagnosis of malignancy are 99.1% and 99.7%, respectively [139] (LE: 2b). However, 0–22.6% of core biopsies are non-diagnostic (8% in the meta-analysis) [133-137, 140, 141, 144] (LE: 2a). If a biopsy is non-diagnostic, and radiologic findings are suspicious for malignancy, a further biopsy or surgical exploration should be considered (LE: 4). Repeat biopsies have been reported to be diagnostic in a high proportion of cases (83-100%) [132, 145-147]. Accuracy of renal tumour biopsies for the diagnosis of tumour histotype is good. The median concordance rate between tumour histotype on renal tumour biopsy and on the surgical specimen of the following PN or RN was 90.3% in the pooled analysis [139]. Assessment of tumour grade on core biopsies is challenging. In the pooled analysis the overall accuracy for nuclear grading was poor (62.5%), but significantly improved (87%) using a simplified two-tier system (high vs. low grade) [139] (LE: 2a). The ideal number and location of core biopsies are not defined. However, at least two good quality cores should be obtained and necrotic areas should be avoided to maximise diagnostic yield [132, 135, 148, 149] (LE: 2b). Peripheral biopsies are preferable for larger tumours, to avoid areas of central necrosis [150] (LE: 2b). In cT2 or greater renal masses, multiple core biopsies taken from at least four separate solid enhancing areas in the tumour were shown to achieve a higher diagnostic yield and a higher accuracy to identify sarcomatoid features, without increasing the complication rate [151]. 5.3.4 Morbidity Overall, percutaneous biopsies have a low morbidity [139]. Tumour seeding along the needle tract has been regarded as anecdotal in large series and pooled analyses on renal tumour biopsies. Especially the coaxial technique has been regarded as a safe method to avoid any seeding of tumour cells. However, authors recently reported on 7 patients in whom tumour seeding was identified on histological examination of the resection specimen after surgical resection of RCC following diagnostic percutaneous biopsy [152]. Six of the 7 cases were of the pRCC type. The clinical significance of these findings is still uncertain but only one of these patients developed local tumour recurrence at the site of the previous biopsy [152]. Spontaneously resolving subcapsular/perinephric haematomas are reported in 4.3% of cases in a pooled analysis, but clinically significant bleeding is unusual (0–1.4%; 0.7% in the pooled analysis) and generally self-limiting [139]. Percutaneous biopsy of renal hilar masses is technically feasible with a diagnostic yield similar to that of cortical masses, but with significantly higher post-procedural bleeding compared with cortical masses [153].

5.4

Summary of evidence and recommendations for the diagnostic assessment of RCC

Summary of evidence Contrast enhanced multi-phasic CT has a high sensitivity and specificity for characterisation and detection of RCC, invasion, tumour thrombus and mRCC. Magnetic resonance imaging has a slightly higher sensitivity and specificity for small cystic renal masses and tumour thrombi as compared to CT. Contrast enhanced ultrasound has a high sensitivity and specificity for characterisation of renal masses. Renal mass biopsies are associated with reduced over-treatment of benign masses and offers patients additional information (i.e. grade, subtype) for an informed decision regarding optimal management. Ultrasound, power-Doppler US and positron-emission tomography CT have a low sensitivity and specificity for detection and characterisation of RCC. Recommendations Use multi-phasic contrast-enhanced computed tomography (CT) of abdomen and chest for the diagnosis and staging of renal tumours. Omit chest CT in patients with incidentally noted cT1a disease due to the low risk of lung metastases in this cohort. Use magnetic resonance imaging (MRI) to better evaluate venous involvement, reduce radiation or avoid intravenous CT contrast medium. Use non-ionising modalities, including MRI and contrast-enhanced ultrasound, for further characterisation of small renal masses, tumour thrombus and differentiation of unclear renal masses, if the results of contrast-enhanced CT are indeterminate.

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LE 2a 2a 2a 3 2a

Strength rating Strong Weak Weak Strong

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Do not routinely use bone scan and/or positron-emission tomography CT for staging of renal cell carcinoma. Perform a renal tumour biopsy before ablative therapy and systemic therapy without previous pathology. Perform a percutaneous biopsy in select patients who are considering active surveillance. Use a coaxial technique when performing a renal tumour biopsy. Do not perform a renal tumour biopsy of cystic renal masses. Use a core biopsy technique rather than fine needle aspiration for histological characterisation of solid renal tumours.

6.

PROGNOSTIC FACTORS

6.1

Classification

Weak Strong Weak Strong Strong Strong

Prognostic factors can be classified into: anatomical, histological, clinical, and molecular.

6.2

Anatomical factors

Tumour size, venous invasion and extension, collecting system invasion, perinephric- and sinus fat invasion, adrenal involvement, and LN and distant metastasis are included in the TNM classification system [154, 155] (Table 4.1).

6.3

Histological factors

Histological factors include tumour grade, RCC subtype, lymphovascular invasion, tumour necrosis, and invasion of the collecting system [156, 157]. Tumour grade is considered one of the most important histological prognostic factors. Fuhrman nuclear grade is based on simultaneous investigation of nuclear size, nuclear shape and nucleolar prominence [158]. It has been the most widely accepted grading system for several decades, but has now been largely replaced by the WHO/ISUP grading classification [159]. This relies solely on nucleolar prominence for grade 1-3 tumours, allowing for less inter-observer variation [160]. It has been shown that the WHO/ISUP grading provides superior prognostic information compared to Fuhrman grading, especially for grade 2 and grade 3 tumours [161]. Rhabdoid and sarcomatoid changes can be found in all RCC types and are equivalent to grade 4 tumours. Sarcomatoid changes are more often found in chRCC than other subtypes [162]. The percentage of the sarcomatoid component appears to be prognostic as well, with a larger percentage of involvement being associated with worse survival. However, there is no agreement on the optimal prognostic cut-off for sub-classifying sarcomatoid changes [163, 164]. The WHO/ISUP grading system is applicable to both ccRCC and pRCC. It is currently not recommended to grade chRCC. However, a recent study suggested a two-tiered chRCC grading system (low vs. high grade) based on the presence of sarcomatoid differentiation and/or tumour necrosis, which was statistically significant on multivariable analysis [165]. Both the WHO/ISUP and chRCC grading systems need to be validated for prognostic systems and nomograms [159]. Renal cell carcinoma subtype is regarded as another important prognostic factor. On univariable analysis, patients with chRCC vs. pRCC vs. ccRCC had a better prognosis [166, 167] (Table 6.1). However, prognostic information provided by the RCC type is lost when stratified according to tumour stage [167, 168] (LE: 3). In a recent cohort study of 1,943 patients with ccRCC and pRCC significant survival differences were only shown between pRCC type I and ccRCC [169]. Papillary RCC has been traditionally divided into type 1 and 2, but a subset of tumours shows mixed features. For more details, see Section 3.2 - Histological diagnosis. Data also suggest that type 2 pRCC is a heterogeneous entity with multiple molecular subgroups [21]. Some studies suggest poorer survival for type 2 than type 1 [170], but this association is often lost in the multivariable analysis [171]. A meta-analysis did not show a significant survival difference between both types [172]. Renal cell carcinoma with Xp11.2 translocation has a poor prognosis [173]. Its incidence is low, but its presence should be systematically assessed in young patients. Renal cell carcinoma type classification has been confirmed by cytogenetic and genetic analyses [174-176] (LE: 2b). Surgically excised malignant complex cystic masses contain ccRCC in the majority of cases, and more than 80% are pT1. In a recent series, 5-year cancer-specific survival (CSS) was 98% [177]. Differences in tumour stage, grade and CSS between RCC types are illustrated in Table 6.1.

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Table 6.1: B  aseline characteristics and cancer-specific survival of surgically treated patients by RCC type [162] Survival time clear-cell RCC papillary RCC chromophobe RCC

% RCC 80 15 5

% Sarcomatoid 5 1 8

% T3-4 33 11 15

% N1 5 5 4

% M1 15 3 4

% 10 year CSS (%) 62 86 86

CSS = cancer-specific survival. In all RCC types, prognosis worsens with stage and histopathological grade (Table 6.2). The 5-year overall survival (OS) for all types of RCC is 49%, which has improved since 2006, probably due to an increase in incidentally detected RCCs and new systemic treatments [178, 179]. Although not considered in the current N classification, the number of metastatic regional LNs is an important predictor of survival in patients without distant metastases [180]. Table 6.2: Cancer-specific survival by stage [20] Grade T1N0M0 T2N0M0 T3N0M0 T4N0M0 N+M0 M+

HR (95% CI) Referent 2.71 (2.17–3.39) 5.20 (4.36–6.21) 16.88 (12.40–22.98) 16.33 (12.89–20.73) 33.23 (28.18–39.18)

CI = confidential interval. HR = hazard ratio.

6.4

Clinical factors

Clinical factors include performance status (PS), local symptoms, cachexia, anaemia, platelet count, neutrophil count, lymphocyte count, C-reactive protein (CRP), albumin, and various indices deriving from these factors such as the neutrophil-to-lymphocyte ratio (NLR) [93, 181-185] (LE: 3). As a marker of systemic inflammatory response, a high pre-operative NLR has been associated with poor prognosis [186], but there is signficant heterogeneity in the data and no agreement on the optimal prognostic cutoff. Even though obesity is an aetiological factor for RCC, it has also been observed to provide prognostic information. A high body mass index (BMI) appears to be associated with improved survival outcomes in both non-metastatic and metastatic RCC [187-189]. This association is linear with regards to cancer-specific mortality, while obese RCC patients show increasing all-cause mortality with increasing BMI [190]. There is also evolving evidence on the prognostic value of body composition indices measured on cross-sectional imaging, such as sarcopenia and fat accumulation [191, 192].

6.5

Molecular factors

Numerous molecular markers such as carbonic anhydrase IX (CaIX), VEGF, hypoxia-inducible factor (HIF), Ki67 (proliferation), p53, p21 [193], PTEN (phosphatase and tensin homolog) cell cycle, E-cadherin, osteopontin [194] CD44 (cell adhesion) [195, 196], CXCR4 [197], PD-L1 [198], miRNA, SNPs, gene mutations, and gene methylations have been investigated (LE: 3) [19]. While the majority of these markers are associated with prognosis and many improve the discrimination of current prognostic models, there has been very little emphasis on external validation studies. Furthermore, there is no conclusive evidence on the value of molecular markers for treatment selection in mRCC [199]. Their routine use in clinical practice is therefore not recommended. Several prognostic and predictive marker signatures have been described for specific systemic treatments in mRCC. In the JAVELIN Renal 101 trial (NCT02684006), a 26-gene immunomodulatory gene signature predicted PFS in those treated with avelumab plus axitinib, while an angiogenesis gene signature was associated with PFS for sunitinib. Mutational profiles and histocompatibility leukocyte antigen (HLA) types were also associated with PFS, while PD-L1 expression and tumour mutational burden were not [200]. In IMmotion151 (NCT02420821), a T effector/IFN-γ-high or angiogenesis-low gene expression signature predicted improved PFS for atezolizumab plus bevacizumab compared to sunitinib. The angiogenesis-high gene expression signature correlated with longer PFS in patients treated with sunitinib [201]. In CheckMate 214 (NCT02231749), a higher angiogenesis gene signature score was associated with better overall response rates and PFS for

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sunitinib, while a lower angiogenesis score was associated with higher ORR in those treated with nivolumab plus ipilimumab. Progression-free survival ≥ 18 months was more often seen in patients with higher expression of Hallmark inflammatory response and Hallmark epithelial mesenchymal transition gene sets [202]. Urinary and plasma Kidney-Injury Molecule-1 (KIM-1) has been identified as a potential diagnostic and prognostic marker. KIM-1 concentrations were found to predict RCC up to 5 years prior to diagnosis and were associated with a shorter survival time [203]. KIM-1 is a glycoprotein marker of acute proximal tubular injury and therefore mainly expressed in RCC derived from the proximal tubules such as ccRCC and pRCC [204]. While early studies are promising, more high-quality research is required. Several retrospective studies and large molecular screening programs have identified mutated genes and chromosomal changes in ccRCC with distinct clinical outcomes. The expression of the BAP1 and PBRM1 genes, situated on chromosome 3p in a region that is deleted in more than 90% of ccRCCs, have shown to be independent prognostic factors for tumour recurrence [205-207]. These published reports suggest that patients with BAP1-mutant tumours have worse outcomes compared with patients with PBRM1-mutant tumours [206]. Loss of chromosome 9p and 14q have been consistently shown to be associated with poorer survival [208-210]. The TRACERx renal consortium has proposed a genetic classification based on RCC evolution (punctuated vs. branched vs. linear), which correlates with tumour aggressiveness and survival [209]. Additionally, a 16-gene signature was shown to predict disease-free survival (DFS) in patients with non-metastatic RCC [211]. However, these signatures have not been validated by independent researchers yet.

6.6

Prognostic models

Prognostic models combining independent prognostic factors have been developed and externally validated [212-218]. These models are more accurate than TNM stage or grade alone for predicting clinically relevant oncological outcomes (LE: 3). Before being adopted, new prognostic models should be evaluated and compared to current prognostic models with regards to discrimination, calibration and net benefit. In metastatic disease, risk groups assigned by the Memorial Sloan Kettering Cancer Center (MSKCC) (primarily created in the pre-targeted therapy, and validated in patients receiving targeted therapy) and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) (initially created in the targeted therapy era) differ in 23% of cases [219]. The IMDC model has been used in the majority of recent randomised trials, including those with immune checkpoint inhibitors, and may therefore be the preferred model for clinical practice. The discrimination of the IMDC model can be improved by addition of a seventh variable, namely presence of brain, bone, and/or liver metastases [220]. For patients treated with immune checkpoint inhibitors, the monocyteto-lymphocyte ratio, BMI, and number and site of metastases at baseline were recently used to create a fourtiered prediction model. This model showed greater discrimination than IMDC in predicting OS, but needs further validation [221]. Overall, there is no conclusive evidence that one prognostic model is superior to another for both localised and metastatic disease [19]. Tables 6.3 and 6.4 summarise the current most relevant prognostic models.

6.7

Summary of evidence and recommendations for prognostic factors

Summary of evidence In RCC patients, TNM stage, tumour size, grade, and RCC subtype provide important prognostic information.

Recommendations Use the current Tumour, Node, Metastasis classification system. Use the WHO/ISUP grading system and classify renal cell carcinoma type. Use prognostic models in localised and metastatic disease. Do not routinely use molecular markers to assess prognosis.

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LE 2a

Strength rating Strong Strong Strong Strong

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Table 6.3: Prognostic models for localised RCC Prognostic model Subtype* Risk factors/prognostic factors UISS** [222] All 1. ECOG PS 2. T classification 3. N classification (N+ classified as metastatic) 4. Grade

Leibovich score/model 2003 [215]

Leibovich score/model 2018 [223]

CC

CC, P, CHR

T1N0M0G1–2, ECOG PS 0: low-risk disease T3N0M0G2–4, ECOG PS ≥ 1 OR T4N0M0: high-risk disease Any other N0M0: intermediate-risk disease 1. T  classification (pT1a: 0 points, pT1b: 1 point, pT2: 3 points, pT3–4: 4 points) 2. N classification (pNx/N0: 0 points, pN+: 2 points) 3. Tumour size (< 10 cm: 0 points, ≥ 10 cm: 1 point) 4. Grade (G1–2: 0 points, G3: 1 point, G4: 3 points) 5. Tumour necrosis (absent: 0 points, present: 1 point) 0–2 points: low-risk disease 3–5 points: intermediate-risk disease 6 or more points: high-risk disease ccRCC • Progression (9 factors): constitutional symptoms, grade, tumour necrosis, sarcomatoid features, tumour size, perinephric or sinus fat invasion, tumour thrombus level, extension beyond kidney, nodal involvement. • Cancer-specific survival (12 factors): age, ECOG PS, constitutional symptoms, adrenalectomy, surgical margins, grade, tumour necrosis, saromatoid features, tumour size, perinephric or sinus fat invasion, tumour thrombus, nodal involvement. • No risk groups/prognostic groups. pRCC • Low risk (group 1): grade 1–2, no fat invasion, no tumour thrombus. • Intermediate risk (group 2): grade 3, no fat invasion, no tumour thrombus. • High risk (group 3): grade 4 or fat invasion or any level tumour thrombus.

VENUSS score/model*** [171]

GRANT score/model**** [224]

P

All

chRCC • Low risk (group 1): no fat invasion, no sarcomatoid differentiation, no nodal involvement. • Intermediate risk (group 2): fat invasion and no sarcomatoid differentiation and no nodal inolvement. • High risk (group 3): sarcomatoid differentiation or nodal involvement. 1. T classification (pT1: 0 points, pT2: 1 point, pT3–4: 2 points) 2. N classification (pNx/pN0: 0 points, pN1: 3 points) 3. Tumour size (≤ 4 cm: 0 points, > 4 cm: 2 points) 4. Grade (G1/2: 0 points, G3/4: 2 points) 5. Tumour thrombus (absent: 0 points, present: 2 points) 0–2 points: low-risk disease 3–5 points: intermediate-risk disease 6 or more points: high-risk disease 1. Age > 60 years 2. T classification = T3b, pT3c or pT4 3. N classification = pN1 4. (Fuhrman) grade = G3 or G4 0–1 factors: favourable-risk disease 2 or more factors: unfavourable-risk disease

* ccRCC = clear-cell RCC; ECOG = Eastern Cooperative Oncology Group; pRCC = papillary RCC; chRCC = chromophobe RCC. ** University of California Integrated Staging system. Available at https://www.mdcalc.com/ucla-integratedstaging-system-uiss-renal-cell-carcinoma-rcc. *** VEnous extension, NUclear grade, Size, Stage. Available at https://evidencio.com/. **** GRade, Age, Nodes and Tumour.

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Table 6.4: Prognostic models for metastatic RCCC Prognostic model Subtype MSKCC [225]** All

IMDC [227]***

All

Risk factors/prognostic factors 1. Karnofsky PS [226]* < 80% 2. Interval from diagnosis to systemic treatment < 1 year 3. Haemoglobin < Lower Limit of Normal 4. Corrected calcium >10 mg/dL/> 2.5 mmol/L 5. LDH > 1.5x Upper Limit of Normal 0 factors: favourable-risk disease 1–2 factors: intermediate-risk disease 3–5 factors: poor-risk disease 1. Karnofsky PS [226]* < 80% 2. Interval from diagnosis to treatment < 1 year 3. Haemoglobin < lower limit of normal 4. Corrected calcium > upper limit of normal (i.e. > 10.2 mg/dL) 5. Neutrophil count > upper limit of normal (i.e. > 7.0×109/L) 6. Platelet count > upper limit of normal (i.e. > 400,000) 0 factors: favourable-risk disease 1–2 factors: intermediate-risk disease 3–6 factors: poor-risk disease

IMDC = International Metastatic Renal Cancer Database Consortium; LDH = lactate dehydrogenase; MSKCC = Memorial Sloan Kettering Cancer Center; PS = performance status. * Karnofsky performance status calculator: https://www.thecalculator.co/health/Karnofsky-Score-forPerformance-Status-Calculator-961.html. ** MSKCC: https://www.mdcalc.com/memorial-sloan-kettering-cancer-center-mskcc-motzer-score-metastaticrenal-cell-carcinoma-rcc. *** IMDC: https://www.mdcalc.com/imdc-international-metastatic-rcc-database-consortium-risk-score-rcc.

7.

DISEASE MANAGEMENT

7.1

Treatment of localised RCC

7.1.1 Introduction Sections 7.1.2 and 7.2.4.2 are underpinned by a systematic review which includes all relevant published literature comparing surgical management of localised RCC (T1-2N0M0). Randomised or quasi-RCTs were included. However, due to the very limited number of RCTs, non-randomised studies (NRS), prospective observational studies with controls, retrospective matched-pair studies, and comparative studies from the databases of well-defined registries were also included. Historically, surgery has been the benchmark for the treatment of localised RCC. 7.1.2 Surgical treatment 7.1.2.1 Nephron-sparing surgery versus radical nephrectomy in localised RCC 7.1.2.1.1 T1 RCC Outcome 1: Cancer-specific survival Most studies comparing the oncological outcomes of PN and RN are retrospective and include cohorts of varied and, overall, limited size [228, 229]. There is only one, prematurely closed, prospective RCT including patients with organ-confined RCCs of limited size (< 5 cm), showing comparable non-inferiority of CSS for PN vs. RN (HR: 2.06 [95% CI: 0.62–6.84]) [230]. Outcomes 2 & 3: Overall mortality and renal function Partial nephrectomy preserved kidney function better after surgery, thereby potentially lowering the risk of development of cardiovascular disorders [228, 231-235]. When compared with a radical surgical approach, several retrospective analyses of large databases have suggested a decreased cardiovascular-specific mortality [232, 236] as well as improved OS for PN compared to RN. However, in some series this held true only for younger patients and/or patients without significant comorbidity at the time of the surgical intervention

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[237, 238]. An analysis of the U.S. Medicare database [239] could not demonstrate an OS benefit for patients ≥ 75 years of age when RN or PN were compared with non-surgical management. Conversely, another series that addressed this question and also included Medicare patients suggested an OS benefit in older patients (75–80 years) when subjected to surgery rather than non-surgical management. Shuch et al. compared patients who underwent PN for RCC with a non-cancer healthy control group via a retrospective database analysis; showing an OS benefit for the cancer cohort [240]. These conflicting results may be an indication that unknown statistical confounders hamper the retrospective analysis of population-based tumour registries. In the only prospectively randomised, but prematurely closed, heavily underpowered, trial, PN seems to be less effective than RN in terms of OS in the intention to treat (ITT) population (HR: 1.50 [95% CI: 1.03–2.16]). However, in the targeted RCC population of the only RCT, the trend in favour of RN was no longer significant [230]. Taken together, the OS advantage suggested for PN vs. RN remains an unresolved issue. Patients with a normal pre-operative renal function and a decreased GFR due to surgical treatment (either RN or PN), generally present with stable long-term renal function [235]. Adverse OS in patients with a pre-existing GFR reduction does not seem to result from further renal function impairment following surgery, but rather from other medical comorbidities causing pre-surgical chronic kidney disease (CKD) [241]. However, in particular in patients with pre-existing CKD, PN is the treatment of choice to limit the risk of development of ESRD which requires haemodialysis. Huang et al. found that 26% of patients with newly diagnosed RCC had an GFR ≤ 60 mL/min, even though their baseline serum creatinine levels were in the normal range [96]. Outcomes 4 & 5: Peri-operative outcomes and quality of life In terms of the intra- and peri-operative morbidity/complications associated with PN vs. RN, the European Organisation for Research and Treatment of Cancer (EORTC) randomised trial showed that PN for small, easily resectable, incidentally discovered RCC, in the presence of a normal contralateral kidney, can be performed safely with slightly higher complication rates than after RN [242]. Only a limited number of studies are available addressing quality of life (QoL) following PN vs. RN, irrespective of the surgical approach used (open vs. minimally invasive). Quality of life was ranked higher following PN as compared to RN, but in general patients’ health status deteriorated following both approaches [242, 243]. In view of the above, and since oncological safety (CSS and RFS) of PN, so far, has been found non-differing from RN outcomes, PN is the treatment of choice for T1 RCC since it preserves kidney function better and in the long term potentially limits the incidence of cardiovascular disorders. Whether decreased mortality from any cause can be attributed to PN is still unresolved, but in patients with pre-existing CKD, PN is the preferred surgical treatment option as it avoids further deterioration of kidney function; the latter being associated with a higher risk of development of ESRD and the need for haemodialysis. Irrespective of the available data, in frail patients, treatment decisions should be individualised, weighing the risks and benefits of PN vs. RN, the increased risk of peri-operative complications and the risk of developing or worsening CKD post-operatively. 7.1.2.1.2 T2 renal cell carcinoma There is very limited evidence on the optimal surgical treatment for patients with larger renal masses (T2). Some retrospective comparative studies of PN vs. RN for T2 RCC have been published [244]. A trend for lower tumour recurrence- and cancer-specific mortality is reported in PN groups. The estimated blood loss is reported to be higher for PN groups, as is the likelihood of post-operative complications [244]. A recent multicentre study compared the survival outcomes in patients with larger (≥ 7 cm) ccRCC treated with PN vs. RN with long-term follow-up (median 102 months). Compared to the RN group, the PN group had a significantly longer median OS (p = 0.014) and median CSS (p = 0.04) [245]. Overall the level of the evidence is low. These studies including T2 masses all have a high risk of selection bias due to imbalance between the PN and RN groups regarding patient’s age, comorbidities, tumour size, stage, and tumour position. These imbalances in covariation factors may have a greater impact on patient outcome than the choice of PN or RN. The Panel’s confidence in the results is limited and the true effects may be substantially different. In view of the above, the risks and benefits of PN should be discussed patients with T2 RCC with a solitary kidney, bilateral renal tumours or CKD, if technically feasible, with sufficient parenchymal volume preserved to allow sufficient post-operative renal function, PN should be considered in these patients. 7.1.2.2 Associated procedures 7.1.2.2.1 Adrenalectomy One prospective non-randomised study compared the outcomes of RN with or without, ipsilateral adrenalectomy [246]. Multivariable analysis showed that upper pole location was not predictive of adrenal involvement, but tumour size was. No difference in OS at 5 or 10 years was seen with, or without, 28

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adrenalectomy. Adrenalectomy was justified using criteria based on radiographic- and intra-operative findings. Only 48 of 2,065 patients underwent concurrent ipsilateral adrenalectomy of which 42 of the 48 interventions were for benign lesions [246]. 7.1.2.2.2 Lymph node dissection for clinically negative lymph nodes (cN0) The indication for LN dissection (LND) together with PN or RN is still controversial [247]. The clinical assessment of LN status is based on the detection of an enlargement of LNs either by CT/MRI or intraoperative palpability of enlarged nodes. Less than 20% of suspected metastatic nodes (cN+) are positive for metastatic disease at histopathological examination (pN+) [248]. Both CT and MRI are unsuitable for detecting malignant disease in nodes of normal shape and size [249]. For clinically positive LNs (cN+) see Section 7.2.2. Smaller retrospective studies have suggested a clinical benefit associated with a more or less extensive LND preferably in patients at high risk for lymphogenic spread. In a large retrospective study, the outcomes of RN with or without LND in patients with high-risk non-mRCC were compared using a propensity score analysis. In this study LND was not significantly associated with a reduced risk of distant metastases, cancer-specific or all-cause mortality. The extent of the LND was not associated with improved oncologic outcomes [250]. The number of LN metastases (< / > 4) as well as the intra- and extracapsular extension of intra-nodal metastasis correlated with the patients´ clinical prognosis in some studies [249, 251-253]. Better survival outcomes were seen in patients with a low number of positive LNs (< 4) and no extranodal extension. On the basis of a retrospective Surveillance, Epidemiology and End Results (SEER) database analysis of > 9,000 patients no effects of an extended LND (eLND) on the disease-specific survival (DSS) of patients with pathologically confined negative nodes was demonstrated [254]. However, in patients with pathologically proven lymphogenic spread (pN+), an increase of 10 for the number of nodes dissected resulted in a 10% absolute increase in DSS. In addition, in a larger cohort of 1,983 patients, Capitanio et al. demonstrated that eLND results in a significant prolongation of CSS in patients with unfavourable prognostic features (e.g., sarcomatoid differentiation, large tumour size) [255]. As to morbidity related to eLND, a recent retrospective propensity score analysis from a large single-centre database showed that eLND is not associated with an increased risk of Clavien grade ≥ 3 complications. Furthermore, LND was not associated with length of hospital stay or estimated blood loss [256]. Only one prospective RCT evaluating the clinical value of LND combined with surgical treatment of primary RCC has been published so far. With an incidence of LN involvement of only 4%, the risk of lymphatic spread appears to be very low. Recognising the latter, only a staging effect was attributed to LND [248]. This trial included a very high percentage of patients with pT2 tumours, which are not at increased risk for LN metastases. Only 25% of patients with pT3 tumours underwent a complete LND and the LN template used by the authors was not clearly stated. The optimal extent of LND remains controversial. Retrospective studies suggest that an eLND should involve the LNs surrounding the ipsilateral great vessel and the inter-aortocaval region from the crus of the diaphragm to the common iliac artery. Involvement of inter-aortocaval LNs without regional hilar involvement is reported in up to 35–45% of cases [249, 257, 258]. At least 15 LNs should be removed [255, 259]. Sentinel LND is an investigational technique [260, 261]. 7.1.2.2.3 Embolisation Before routine nephrectomy, tumour embolisation has no benefit [262, 263]. In patients unfit for surgery, or with non-resectable disease, embolisation can control symptoms, including visible haematuria or flank pain [264, 265]. These indications will be revisited in Sections 7.2 and 7.3 with cross reference to the summary of evidence and recommendations below. 7.1.2.2.4 Summary of evidence and recommendations for the treatment of localised RCC Summary of evidence The oncological outcome in terms of OS following PN equals that of RN in patients with c/p T1 RCC. Retrospective studies suggest that oncological outcomes are similar following PN vs. RN in patients with larger (≥ 7 cm) RCC. Post-operative complication rates are higher in PN patients. Ipsilateral adrenalectomy during RN or PN has no survival advantage in the absence of clinically evident adrenal involvement. In patients with localised disease without radiographic evidence of LN metastases, a survival advantage of LND in conjunction with RN is not demonstrated in randomised trials. Retrospective studies suggest a clinical benefit associated with lymphadenectomy in high-risk patients. In patients unfit for surgery with massive haematuria or flank pain, embolisation can be a beneficial palliative approach.

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LE 1b 3b 3 2b 2b 3

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Recommendations Offer surgery to achieve cure in localised renal cell cancer. Offer partial nephrectomy (PN) to patients with T1 tumours. Offer PN to patients with T2 tumours and a solitary kidney or chronic kidney disease, if technically feasible. Do not perform ipsilateral adrenalectomy if there is no clinical evidence of invasion of the adrenal gland. Do not offer an extended lymph node dissection to patients with organ-confined disease. Offer embolisation to patients unfit for surgery presenting with massive haematuria or flank pain.

Strength rating Strong Strong Weak Strong Weak Weak

7.1.3 Radical and partial nephrectomy techniques 7.1.3.1 Radical nephrectomy techniques No RCTs have assessed the oncological outcomes of laparoscopic vs. open RN. A cohort study [266] and retrospective database reviews are available, mostly of low methodological quality, showing similar oncological outcomes even for higher stage disease and locally more advanced tumours [267-269]. Based on a systematic review, less morbidity was found for laparoscopic vs. open RN [228]. Data from one RCT [268] and two non-randomised studies [270, 271] showed a significantly shorter hospital stay and lower analgesic requirement for the laparoscopic RN group as compared with the open group. Convalescence time was also significantly shorter [271]. No difference in the number of patients receiving blood transfusions was observed, but peri-operative blood loss was significantly less in the laparoscopic arm in all 3 studies [268, 270, 271]. Surgical complication rates were low with very wide confidence intervals. There was no difference in complications, but operation time was significantly shorter in the open nephrectomy arm. Post-operative QoL scores were similar [270]. Some comparative studies focused on the peri-operative outcomes of laparoscopic vs. RN for renal ≥ T2 tumours. Overall, patients who underwent laparoscopic RN were shown to have lower estimated blood loss, less post-operative pain, shorter length of hospital stay and convalescence compared to those who underwent open RN [269, 271, 272]. Intra-operative and post-operative complications were similar in the two groups and no significant differences in CSS, PFS and OS were reported [269, 271, 272] (LE: 2b). Another multicentre propensity matched analysis compared laparoscopic- and open surgery for pT3a RCC, showing no significant difference in 3-year RFS between groups [273]. The best approach for laparoscopic RN was the retroperitoneal or transperitoneal approach with similar oncological outcomes in two RTCs [274, 275] and one quasi-randomised study [276]. Quality of life variables were similar for both approaches. Hand-assisted vs. standard laparoscopic RN was compared in one quasi-randomised study [276] and one database review and estimated 5-year OS, CSS, and RFS rates were comparable [277]. Duration of surgery was significantly shorter in the hand-assisted approach, while length of hospital stay and time to non-strenuous activities were shorter for the standard laparoscopic RN cohort [276, 277]. However, the sample size was small. Data of a large retrospective cohort study on robot-assisted laparoscopic vs. laparoscopic RN showed robotic-assisted laparoscopic RN was not associated with increased risk of any or major complications but had a longer operating time and higher hospital costs compared with laparoscopic RN [278]. A systematic review reported on robot-assisted laparoscopic vs. conventional laparoscopic RN, showing no substantial differences in local recurrence rates, nor in all-cause cancer-specific mortality [279]. Similar results were seen in observational cohort studies comparing ‘portless’ and 3-port laparoscopic RN, with similar perioperative outcomes [280, 281]. 7.1.3.2 Partial nephrectomy techniques 7.1.3.2.1 Open versus laparoscopic approach Studies comparing laparoscopic and open PN found no difference in PFS [282-285] and OS [284, 285] in centres with laparoscopic expertise. However, the oncological safety of laparoscopic vs. open PN has, so far, only been addressed in studies with relatively limited follow-up [273]. However, the higher number of patients treated with open surgery in this series might reflect a selection bias by offering laparoscopic surgery in case of a less complex anatomy [273]. The mean estimated blood loss was found to be lower with the laparoscopic approach [282, 284, 286], while post-operative mortality, deep vein thrombosis, and pulmonary embolism events were similar [282, 284]. Operative time is generally longer with the laparoscopic approach [283-285] and warm ischaemia time is shorter with the open approach [282, 284, 286, 287]. In a matched-pair comparison, GFR decline was greater in the laparoscopic PN group in the immediate post-operative period [285], but not after 3.6 years follow-up. In another comparative study, the surgical approach was not an independent predictor for post-operative CKD [287]. Retroperitoneal and transperitoneal laparoscopic PN have similar peri-operative outcomes [288]. Simple tumour enucleation also had similar PFS and CSS rates compared to

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standard PN and RN in a large study [289]. The feasibility of laparo-endoscopic single-site PN has been shown in selected patients but larger studies are needed to confirm its safety and clinical role [290]. 7.1.3.2.2 Open versus robotic approach One study prospectively compared the peri-operative outcomes of a series of robot-assisted and open PN performed by the same experienced surgeon. Robot-assisted PN was superior to open PN in terms of lower estimated blood loss and shorter hospital stay. Warm ischaemia time, operative time, immediate- early- and short-term complications, variation in creatinine levels and pathologic margins were similar between groups [291]. A multicentre French prospective database compared the outcomes of 1,800 patients who underwent open PN and robot-assisted PN. Although the follow-up was shorter, there was a decreased morbidity in the robotic-assisted PN group with less overall complications, less major complications, less transfusions and a much shorter hospital stay [292]. 7.1.3.2.3 Open versus hand-assisted approach Hand-assisted laparoscopic PN (HALPN) is rarely performed. A recent comparative study of open vs. HALPN showed no difference in OS or RFS at intermediate-term follow-up. The authors observed a lower rate of intraoperative and all-grade post-operative 30-day complications in HALPN vs. open PN patients, but there was no significant difference in high Clavien grade complications. Three months after the operation, GFR was lower in the HALPN than in the open PN group [293]. 7.1.3.2.4 Open versus laparoscopic versus robotic approaches In a retrospective propensity-score-matched study, comparing open-, laparoscopic- and robot-assisted PN, after 5-year of median follow-up, similar rates of local recurrence, distant metastasis and cancer-related death rates were found [294]. 7.1.3.2.5 Laparoscopic versus robotic approach Another study included the 50 last patients having undergone laparoscopic and robotic PN for T1-T2 renal tumours by two different surgeons with an experience of over 200 procedures each in laparoscopic and robotic PN and robotic-assisted partial nephrectomy (RAPN), respectively, at the beginning of the study. Peri-operative and short-term oncological and functional outcomes appeared broadly comparable between RAPN and LPN when performed by highly experienced surgeons [295]. A meta-analysis, including a series of NSS with variable methodological quality compared the peri-operative outcomes of robot-assisted- and laparoscopic PN. The robotic group had a significantly lower rate of conversion to open surgery and to radical surgery, shorter warm ischaemia time, smaller change in estimated GFR after surgery and shorter length of hospital stay. No significant differences were observed between the two groups regarding complications, change of serum creatinine after surgery, operative time, estimated blood loss and positive surgical margins [296]. 7.1.3.2.6 Surgical volume In a recent analysis of 8,753 patients who underwent PN, an inverse non-linear relationship of hospital volume with morbidity of PN was observed, with a plateauing seen at 35 to 40 cases per year overall, and 18 to 20 cases for the robotic approach [297]. A retrospective study of a U.S. National Cancer Database looked at the prognostic impact of hospital volume and the outcomes of robot-assisted PN, including 18,724 cases. This study shows that undergoing RAPN at higher-volume hospitals may have better peri-operative outcomes (conversion to open and length of hospital stay) and lower positive surgical margin rates [298]. A French study, including 1,222 RAPN patients, has shown that hospital volume is the main predictive factor of Trifecta achievement (no complications, warm ischaemia time < 25 min, and negative surgical margins) after adjustment for other variables, including surgeon volume [299]. The prospective REgistry of COnservative and Radical Surgery for cortical renal tumour Disease (RECORd-2) study including 2,076 patients showed that the hospital volume (> 60 PN/year) is an independent predictor for positive surgical margins [300]. 7.1.3.3 Positive surgical margins on histopathological specimens A positive surgical margin is encountered in about 2–8% of PNs [296]. Studies comparing surgical margins with different surgical approaches (open, laparoscopic, robotic) are inconclusive [301, 302]. Most trials showed that intra-operative frozen section analysis had no influence on the risk of definite positive surgical margins [303]. A positive surgical margin status occurs more frequently in cases in which surgery is imperative (solitary kidneys and bilateral tumours) and in patients with adverse pathological features (pT2a, pT3a, grade III-IV) [304-307]. The potential negative impact of a positive margin status on the oncologic outcome is still controversial [301].

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The majority of retrospective analyses reported so far indicated that positive surgical margins do not translate into a higher risk of metastases or a decreased CSS [305, 306]. On the other hand, another retrospective study of a large single institutional series showed that positive surgical margins are an independent predictor of PFS due to a higher incidence of distant and local relapses [308]. However, only a proportion of patients with an uncertain margin status actually harbour residual malignancy [309]. Local tumour bed recurrences were found in 16% in patients with positive surgical margins compared with 3% in those with negative margins [304], Therefore, RN or re-resection of margins can result in over-treatment in many cases. Patients with positive surgical margins should be informed that they will need a more intense surveillance (imaging) follow-up and that they are at increased risk of secondary local therapies [305, 310]. On the other hand, protection from recurrence is not ensured by negative surgical margins [311]. 7.1.3.4

Summary of evidence and recommendations for radical and partial nephrectomy techniques

Summary of evidence Laparoscopic radical nephrectomy (RN) has lower morbidity than open nephrectomy. Short-term oncological outcomes for T1-T2a tumours are equivalent for laparoscopic and open RN. Partial nephrectomy can be performed, either by open-, pure laparoscopic- or robot-assisted approach, based on surgeon’s expertise and skills. Robotic-assisted and laparoscopic PN are associated with shorter length of hospital stay and lower blood loss compared to open PN. Partial nephrectomy is associated with a higher percentage of positive surgical margins compared to RN. Hospital volume in PN might impact on surgical complications, warm ischaemia and surgical margins. Radical nephrectomy after positive surgical margins can result in over-treatment in many cases. Recommendations Offer laparoscopic radical nephrectomy (RN) to patients with T2 tumours and localised masses not treatable by partial nephrectomy (PN). Do not perform minimally invasive RN in patients with T1 tumours for whom a PN is feasible by any approach, including open. Do not perform minimally invasive surgery if this approach may compromise oncological-, functional- and peri-operative outcomes. Intensify follow-up in patients with a positive surgical margin.

LE 1b 2a 2b 2b 3 3 3

Strength rating Strong Strong Strong Weak

7.1.4 Therapeutic approaches as alternatives to surgery 7.1.4.1 Surgical versus non-surgical treatment Population-based studies compared the oncological outcomes of surgery (RN or PN) and non-surgical management for tumours < 4 cm. The analyses showed a significantly lower cancer-specific mortality in patients treated with surgery [239, 312, 313]. However, the patients assigned to the surveillance arm were older and likely to be frailer and less suitable for surgery. Other-cause mortality rates in the non-surgical group significantly exceeded that of the surgical group [312]. Analyses of older patients (> 75 years) failed to show the same benefit in cancer-specific mortality for surgical treatment [314-316]. 7.1.4.2 Active surveillance and watchful waiting Elderly and comorbid patients with incidental small renal masses have a low RCC-specific mortality and significant competing-cause mortality [317, 318]. Active surveillance is defined as the initial monitoring of tumour size by serial abdominal imaging (US, CT, or MRI) with delayed intervention reserved for tumours showing clinical progression during follow-up [319]. The concept of AS differs from the concept of watchful waiting; watchful waiting is reserved for patients whose comorbidities contraindicate any subsequent active treatment and do not require follow-up imaging, unless clinically indicated. In the largest reported series of AS the growth of renal tumours was low and progression to metastatic disease was reported in only a limited number of patients [320, 321]. A single-institutional comparative study evaluating patients aged > 75 years showed decreased OS for those who underwent surveillance and nephrectomy relative to NSS for clinically T1 renal tumours. However, at multivariate analysis, management type was not associated with OS after adjusting for age, comorbidities, and other variables [317]. No statistically significant differences in OS and CSS were observed in another study of RN vs. PN vs. AS for T1a renal masses with a follow-up of 34 months [322]. The prospective non-randomised multi-institutional Delayed Intervention and Surveillance for Small Renal Masses (DISSRM)

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study enrolled 497 patients with solid renal masses < 4 cm who selected either AS or primary active intervention. Patients who selected AS were older, had worse ECOG scores, more comorbidities, smaller tumours, and more often had multiple and bilateral lesions. In patients who elected AS in this study the overall median small renal mass growth rate was 0.09 cm/year with a median follow-up of 1.83 years. The growth rate and variability decreased with longer follow-up. No patients developed metastatic disease or died of RCC [323, 324]. Overall survival for primary intervention and AS was 98% and 96% at 2 years, and 92% and 75% at 5 years, respectively (p = 0.06). At 5 years, CSS was 99% and 100%, respectively (p = 0.3). Active surveillance was not predictive of OS or CSS in regression modelling with relatively short follow-up [323]. Overall, both short- and intermediate-term oncological outcomes indicate that in selected patients with advanced age and/ or comorbidities, AS is appropriate for initially monitoring of small renal masses, followed, if required, by treatment for progression [319-321, 325-328]. A multicentre study assessed QoL of patients undergoing immediate intervention vs. AS. Patients undergoing immediate intervention had higher QoL scores at baseline, specifically for physical health. The perceived benefit in physical health persisted for at least one year following intervention. Mental health, which includes domains of depression and anxiety, was not adversely affected while on AS [329]. 7.1.4.3 Role of renal tumour biopsy before active surveillance Histological characterisation of small renal masses by renal tumour biopsy is useful to select tumours at lower risk of progression based on grade and histotype, which can be safely managed with AS. Pathology can also help to tailor surveillance imaging schedules. In the largest cohort of biopsy-proven, small, sporadic RCCs followed with AS a significant difference in growth and progression among different RCC subtypes was observed. Clear-cell RCC small renal masses grew faster than papillary type 1 small renal masses (0.25 and 0.02 cm/year on average, respectively, p = 0.0003) [330]. 7.1.4.4 Tumour ablation 7.1.4.4.1 Role of renal mass biopsy A RMB is required prior to tumour ablation (TA) (see Sections 5.3 Renal tumour biopsy and 5.4 Summary of evidence and recommendations for the diagnostic assessment of RCC). Historically, up to 45% of patients underwent TA of a benign or non-diagnostic mass [331, 332]. A RMB in a separate session reduces over-treatment significantly, with 80% of patients with benign lesions opting not to proceed with TA [332]. Additionally, there is some evidence that the oncological outcome following TA differs according to RCC subtype which should therefore be factored into the decision-making process. In a series of 229 patients with cT1a tumours (mean size 2.5 cm) treated with RFA, the 5-year DFS rate was 90% for ccRCC and 100% for pRCC (80 months: 100% vs. 87%, p = 0.04) [333]. In another series, the total TA effectiveness rate was 90.9% for ccRCC and 100% for pRCC [334]. A study comparing RFA with surgery suggested worse outcomes of RFA vs. PN in cT1b ccRCC, while no difference was seen in those with non-ccRCC [335]. Furthermore, patients with high-grade RCC or metastasis may choose different treatments over TA. Finally, patients without biopsy or a non-diagnostic biopsy are often assumed to have RCC and will undergo potentially unnecessary radiological follow-up or further treatment. 7.1.4.4.2 Cryoablation Cryoablation is performed using either a percutaneous- or a laparoscopic-assisted approach, with technical success rates of > 95% [336]. In comparative studies, there was no significant difference in the overall complication rates between laparoscopic- and percutaneous cryoablation [337-339]. One comparative study reported similar OS, CSS, and RFS in 145 laparoscopic patients with a longer follow-up vs. 118 patients treated percutaneously with a shorter follow-up [338]. A shorter average length of hospital stay was found with the percutaneous technique [338-340]. A systematic review including 82 articles reported complication rates ranging between 8 and 20% with most complications being minor [341]. Although a precise definition of tumour recurrence is lacking, the authors reported a lower RFS as compared to that of PN. Oncological outcomes after cryoablation have generally been favourable for cT1a tumours. In a recently published series of 308 patients with cT1a and cT1b tumours undergoing percutaneous cryoablation, local recurrence was seen in 7.7% of cT1a tumours vs. 34.5% of cT1b tumours. Disease-free survival for the entire cohort was 92.5% at 1 year, 89.3% at 2 years, and 86.7% at 3 years. On multivariable regression, the risk of disease progression increased by 32% with each 1 cm increase in tumour size (HR: 1.32, p < 0.001). Mean decline in eGFR was 11.7 mL/min/1.73 m2 [342]. In another large series of 220 patients with biopsy proven cT1 RCC, 5-year local RFS was 93.9%, while metastasis-free survival approached 94.4% [336]. For cT1b tumours, local tumour control rates drop significantly. One study showed local tumour control in only 60.3% at 3 years [343]. In another series, the PFS rate was 66.7% at 12 months [344].

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Furthermore, recent analyses demonstrated 5-year cancer-specific mortality rates of 7.6–9% [345, 346]. On multivariable analysis, cryoablation of cT1b tumours was associated a 2.5-fold increased risk of death from RCC compared with PN [345]. Recurrence after initial cryoablation is often managed with re-cryoablation, but only 45% of patients remain disease-free at 2 years [347]. 7.1.4.4.3 Radiofrequency ablation Radiofrequency ablation is performed laparoscopically or percutaneously. Several studies compared patients with cT1a tumours treated by laparoscopic or percutaneous RFA [348-351]. Complications occurred in up to 29% of patients but were mostly minor. Complication rates, recurrence rates and CSS were similar in patients treated laparoscopically and percutaneously. The initial technical success rate on early (i.e. 1 month) imaging after one session of RFA is 94% for cT1a and 81% for cT1b tumours [352]. This is generally managed by re-RFA, approaching overall total technical success rates > 95% with one or more sessions [353]. Long-term outcomes with over five years of follow-up following RFA have been reported. In recent studies, the 5-year OS rate was 73–79% [352, 353], due to patient selection. Oncological outcomes for cT1a tumours have been favourable. In a recent study, the 10-year disease-free survival rate was 82%, but there was a significant drop to 68% for tumours > 3 cm [353]. In series focusing on clinical T1b tumours (4.1–7.0 cm), the 5-year DFS rate was 74.5% to 81% [352, 354]. Oncological outcomes appear to be worse than after surgery, but comparative data are severely biased (see Section 7.1.4.3.4). In general, most disease recurrences occur locally and recurrences beyond five years are rare [353, 354]. 7.1.4.4.4 Tumour ablation versus surgery The Guideline Panel performed a protocol-driven systematic review of comparative studies (including > 50 patients) of TA with PN for T1N0M0 renal masses [7]. Twenty-six non-randomised comparative studies published between 2000 and 2019 were included, recruiting a total of 16,780 patients. Four studies compared laparoscopic TA vs. laparoscopic/robotic PN; 16 studies compared laparoscopic or percutaneous TA vs. open-, laparoscopic- or robotic PN; 2 studies compared different techniques of TA and 4 studies compared TA vs. PN vs RN. In this systematic review, TA as treatment for T1 renal masses was found to be safe in terms of complications and adverse events, but its long-term oncological effectiveness compared with PN remained unclear. The primary reason for the persisting uncertainty was related to the nature of the available data; most studies were retrospective observational studies with poorly matched controls, or single-arm case series with short follow-up. Many studies were poorly described and lacked a clear comparator. There was also considerable methodological heterogeneity. Another major limitation was the absence of clearly defined primary outcome measures. Even when a clear endpoint such as OS was reported, data were difficult to interpret because of the varying length and type of follow-up amongst studies. The Panel also appraised the published systematic reviews based on the AMSTAR 2 tool which showed critically low or low ratings [7]. Tumour ablation has been demonstrated to be associated with good long-term survival in several single-arm non-comparative studies [355, 356]. Due to the lack of controls, this apparent benefit is subject to significant uncertainties. Whether such benefit is due to the favourable natural history of such tumours or due to the therapeutic efficacy of TA, as compared to PN, remains unknown. In addition, there are data from comparative studies suggesting TA may be associated with worse oncological outcomes in terms of local recurrence and metastatic progression and cancer-specific mortality [237, 345, 346, 357, 358]. However, there appears to be no clinically significant difference in 5-year cancer-specific mortality between TA and AS [313]. The Panel concluded that the current data are inadequate to reach conclusions regarding the clinical effectiveness of TA as compared with PN. Given these uncertainties in the presence of only low-quality evidence, TA can only be recommended to frail and/or comorbid patients with small renal masses. 7.1.4.4.5 Stereotactic ablative radiotherapy Stereotactic ablative radiotherapy (SABR) has been emerging as a treatment option for medically inoperable patients with localised cT1a and cT1b tumours. Patients usually receive 26 Gy in a single fraction, three fractions of 14 Gy or five fractions of 6 Gy [359, 360]. In a systematic review or non-comparative single-arm studies, the local control rate was 97.2% and the mean change in eGFR was 7.7 mL/min/1.73 m2. Grade 3 or 4 toxicities occurred in 1.5% of patients. However, viable tumour cells are often seen in post-SABR biopsies, although their clinical significance remains unclear [360]. Although early results of SABR are encouraging, more evidence from randomised trials is needed.

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7.1.4.4.6 Other ablative techniques Some studies have shown the feasibility of other ablative techniques, such as microwave ablation, highintensity focused US ablation and non-thermal irreversible electroporation. However, these techniques are still considered experimental. The best evidence base for these techniques exists for percutaneous microwave ablation. In a study of 185 patients with a median follow-up of 40 months, the 5-year local progression rate was 3.2%, while 4.3% developed distant metastases [361]. Results appear to be favourable for cT1b tumours as well [362]. Overall, current data on cryoablation, RFA and microwave ablation of cT1a renal tumours indicate short-term equivalence with regards to complications, oncological and renal functional outcomes [363]. 7.1.4.4.7 Summary of evidence and recommendation for therapeutic approaches as alternative to surgery Summary of evidence Most population-based analyses show a significantly lower cancer-specific mortality for patients treated with surgery compared to non-surgical management. In AS cohorts, the growth of small renal masses is low in most cases and progression to metastatic disease is rare (1–2%). Low quality studies suggest high disease recurrence rates after RFA of tumours > 3 cm and after cryoablation of tumours > 4 cm. Low quality studies suggest a higher local recurrence rate for TA therapies compared to PN, but the quality of data does not allow definitive conclusions. Recommendation Offer active surveillance (AS) or thermal ablation (TA) to frail and/or comorbid patients with small renal masses. Perform a percutaneous renal mass biopsy prior to, and not concomitantly with, TA. When TA or AS are offered, discuss with patients about the harms/benefits with regards to oncological outcomes and complications. Do not routinely offer TA for tumours > 3 cm and cryoablation for tumours > 4 cm.

7.2

LE 3 3 3 3

Strength rating Weak Strong Strong Weak

Treatment of locally advanced RCC

7.2.1 Introduction In addition to the summary of evidence and recommendations outlined in Section 7.1 for localised RCC, certain therapeutic strategies arise in specific situations for locally advanced disease. 7.2.2 Role of lymph node invasion in locally advanced RCC In locally advanced RCC, the role of LND is still controversial. The only available RCT demonstrated no survival benefit for patients undergoing LND but this trial mainly included organ-confined disease cases [248]. In the setting of locally advanced disease, several papers addressed the topic with contradictory results, as did several systematic reviews. Bhindi et al. could not confirm any survival benefit in patients at high risk of progression treated with LND [364]. More recently, Luo et al. reported a systematic review and meta-analyses showing a survival benefit in patients with locally advanced disease treated with LND [365]. More specifically, thirteen studies on patients with LND and non-LND were identified and included in the analysis. In the subgroup of locally advanced RCC (cT3-T4NxM0), LND showed a significantly better OS rate in patients who had undergone LND compared to those without LND (HR: 0.73, 95% CI: 0.60–0.90, p = 0.003). 7.2.2.1 Management of clinically negative lymph nodes (cN-) in locally advanced RCC In case of cN-, the probability of finding pathologically confirmed LN metastases ranges between 0 and 25%, depending mainly on primary tumour size and the presence of distant metastases [366]. In case of clinically negative LNs (cN-) at imaging, removal of LNs is justified only if visible or palpable during surgery [367], at least for staging, prognosis and follow-up implications although a benefit in terms of cancer control has not yet been demonstrated [250, 364]. Whether to extend the LND also to retroperitoneal areas without cN+ remains controversial [249]. 7.2.2.2 Management of clinically positive lymph nodes (cN+) in locally advanced RCC In case of cN+, the probability to find pathologically confirmed LN metastases ranges between 10.3% (cT1 tumours) up to 54.5% in case of locally advanced disease. In cN+, removal of visible and palpable nodes during lymphadenectomy is always justified [367], at least for staging, prognosis and follow-up implications, although a benefit in terms of cancer control has not yet been demonstrated [250, 364].

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7.2.3 Management of locally advanced unresectable RCC In case of locally advanced unresectable RCC, a multidisciplinary evaluation, including urologists, medical oncologists and radiation therapists is suggested to maximise cancer control, pain control and the best supportive care. In patients with non-resectable disease, embolisation can control symptoms, including visible haematuria or flank pain [264, 265, 368]. The use of systemic therapy to downsize tumours is experimental and cannot be recommended outside clinical trials. 7.2.4 Management of RCC with venous tumour thrombus Tumour thrombus formation in RCC patients is a significant adverse prognostic factor. Traditionally, patients with venous tumour thrombus undergo surgery to remove the kidney and tumour thrombus. Aggressive surgical resection is widely accepted as the default management option for patients with venous tumour thrombus [369-377]. 7.2.4.1 The evidence base for surgery in patients with venous tumour thrombus Data whether patients with venous tumour thrombus should undergo surgery is derived from case series only. In one of the largest published studies a higher level of thrombus was not associated with increased tumour dissemination to LNs, perinephric fat or distant metastasis [374]. Therefore, all patients with non-metastatic disease and venous tumour thrombus, and an acceptable PS, should be considered for surgical intervention, irrespective of the extent of tumour thrombus at presentation. The surgical technique and approach for each case should be selected based on the extent of tumour thrombus. 7.2.4.2 The evidence base for different surgical strategies A systematic review was undertaken which included only comparative studies on the management of venous tumour thrombus in non-metastatic RCC [378, 379]. Only 5 studies were eligible for final inclusion, with a high risk of bias across all studies. Minimal access techniques resulted in significantly shorter operating time compared with traditional median sternotomy [380, 381]. No significant differences in oncological and process outcomes were observed between cardiopulmonary bypass with deep hypothermic circulatory arrest or partial bypass under normothermia or single caval clamp without circulatory support [382]. No surgical method was shown to be superior for the excision of venous tumour thrombus. The surgical method selected depended on the level of tumour thrombus and the grade of occlusion of the IVC [378, 380-382]. The relative benefits and harms of other strategies and approaches regarding access to the IVC and the role of IVC filters and bypass procedures remain uncertain. 7.2.4.3

Summary of evidence and recommendations for the management of RCC with venous tumour thrombus

Summary of evidence In patients with locally advanced disease, the survival benefit of LN dissection is unproven but LN dissection has significant staging, prognosis and follow-up implications. Low quality data suggest that tumour thrombus excision in non-metastatic disease may be beneficial.

Recommendations In patients with clinically enlarged lymph nodes (LNs), perform LN dissection for staging, prognosis and follow-up implications. Remove the renal tumour and thrombus in case of venous involvement in non-metastatic disease. In case of metastatic disease, discuss surgery within the context of a multidisciplinary team.

LE 3 3

Strength rating Weak Strong Weak

7.2.5 Neoadjuvant and adjuvant therapy Neoadjuvant therapy is currently under investigation and available in clinical trials. There is currently no evidence from a recent systematic review (including ten retrospective studies and two RCTs) that adjuvant radiation therapy increases survival [383]. Similarly, there is currently no evidence from randomised phase III trials that medical adjuvant therapy offers a survival benefit. The impact on OS of adjuvant tumour vaccination in selected patients undergoing nephrectomy for T3 renal carcinomas remains unconfirmed [384-388] (LE: 1b). Results from prior adjuvant trials studying interferon-alpha (IFN-α) and interleukin-2 (IL-2) did not show a survival benefit [389]. A similar observation was made in an adjuvant trial of girentuximab, a monoclonal antibody against carboanhydrase IX (CAIX) (ARISER Study) [390]. 36

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At present, there is no OS data supporting the use of adjuvant VEGFR or mTOR inhibitors. Thus far, several RCTs comparing VEGFR-TKI vs. placebo have been published. One of the largest adjuvant trials compared sunitinib vs. sorafenib vs. placebo (ASSURE). Its interim results published in 2015 demonstrated no significant differences in DFS or OS between the experimental arms and placebo [391]. The study published its updated analysis on a subset of high-risk patients in 2018, which demonstrated 5-year DFS rates of 47.7%, 49.9%, and 50.0%, respectively for sunitinib, sorafenib, and placebo (HR: 0.94 for sunitinib vs. placebo; and HR: 0.90, 97.5% CI: 0.71–1.14 for sorafenib vs. placebo), and 5-year OS of 75.2%, 80.2%, and 76.5% (HR: 1.06, 97.5% CI: 0.78–1.45, p = 0.66, for sunitinib vs. placebo; and HR: 0.80; 97.5% CI: 0.58–1.11, p = 0.12 for sorafenib vs. placebo). The results indicated that adjuvant therapy with sunitinib or sorafenib should not be given [392]. The PROTECT study included 1,135 patients treated with pazopanib (n = 571) vs. placebo (n = 564) in a 1:1 randomisation [393]. The primary endpoint was amended after 403 patients received a starting dose of pazopanib 800 mg vs. placebo, to DFS with pazopanib 600 mg. The primary analysis results of DFS in the intention to treat (ITT) pazopanib 600 mg arm were not significant (HR: 0.86, 95% CI: 0.7–1.06, p = 0.16). Disease-free survival in the ITT pazopanib 800 mg population was improved (HR: 0.69, 95% CI: 0.51–0.94, p = 0.02). No benefit in OS was seen in the ITT pazopanib 600 mg population (HR: 0.79 [0.57–1.09, p = 0.16]). A subset analysis of these studies suggests that full-dose therapy is associated with improved DFS. Furthermore, no strong association of DFS with OS has been established [394, 395]. The ATLAS study, a randomised, double-blind phase III trial including patients receiving (1:1) oral twice-daily axitinib 5 mg or placebo for ≤ 3 years, for a minimum of one year unless patients experienced a recurrence, had a second primary malignancy, significant toxicity, or withdrew consent. The primary endpoint was DFS. A total of 724 patients (363 vs. 361, for axitinib vs. placebo) were randomised. The trial was stopped due to futility at a preplanned interim analysis at 203 DFS events. There was no significant difference in DFS per independent review committee (IRC) (HR: 0.870, 95% CI: 0.660–1.147, p=0.3211). In the highest-risk subpopulation, a 36% and 27% reduction in risk of a DFS event (HR; 95% CI) was observed per investigator (HR: 0.641, 95% CI: 0.468–0.879, p = 0.0051) and by IRC (HR: 0.735, 95% CI: 0.525–1.028, p = 0.0704), respectively. Overall survival data were not mature. Similar adverse events (AEs; 99% vs. 92%) and serious AEs (19% vs. 14%), but more grade 3/4 AEs (61% vs. 30%) were reported for axitinib vs. placebo [396]. In contrast, the S-TRAC study included 615 patients randomised to either sunitinib or placebo [397]. The results showed a benefit of sunitinib over placebo for DFS (HR: 0.76, 95% CI: 0.59–0.98, p = 0.03). Grade 3/4 toxicity in the study was 60.5% for patients receiving sunitinib, which translated into significant differences in QoL for loss of appetite and diarrhoea. The study published its updated results in 2018; the results for DFS had not changed significantly (HR: 0.74, 95% CI: 0.55–0.99, p = 0.04) and median OS was not reached in either arm (HR: 0.92, 95% CI: 0.66–1.28, p = 0.6). To date, the results of two RCTs on the role of adjuvant sorafenib (SORCE) and everolimus (EVEREST) in patients with RCC are still awaited. Their findings may provide additional insight into the role of adjuvant targeted therapy in RCC. A recent meta-analysis of phase III randomised clinical trials on adjuvant TKIs in ccRCC was published [398]. In the overall population, the pooled HR of OS and DFS was 0.89 (95% CI: 0.76–1.04) and 0.84 (95% CI: 0.76– 0.93), respectively. In the low- and high-risk populations, the pooled DFS HR was 0.98 (95% CI: 0.82–1.17) and 0.85 (95% CI: 0.75–0.97), respectively. Adjuvant use of TKIs does not appear to provide a statistically significant OS benefit. However, a benefit in DFS has been observed in overall and high-risk populations, suggesting that better selection of patients might be important for the evaluation of adjuvant therapies in RCC, although these results must be balanced against significant toxicity. In summary, there is currently a lack of proven benefits of adjuvant therapy with VEGFR-TKIs for patients with high-risk RCC after nephrectomy. The European Medicines Agency (EMA) has not approved sunitinib for adjuvant treatment of high-risk RCC in adult patients after nephrectomy. Immune checkpoint inhibitors, designed to restore and enhance immune activity against cancer cells, have shown impressive efficacy in the metastatic setting. Several trials have tested these agents in metastatic RCC, leading to a still-ongoing revolution in the treatment pathway. The inclusion of these drugs in clinical practice has led to a third generation of adjuvant studies on immune checkpoint inhibitors. These include the programmed death receptor-1 inhibitors nivolumab (PROSPER; NCT03055013), pembrolizumab (KEYNOTE-564; NCT03142334), as well as the programmed death ligand-1 inhibitors atezolizumab (IMmotion010; NCT03024996) and durvalumab (RAMPART [Renal Adjuvant MultiPle Arm Randomised Trial]; NCT03288532). Recruitment for most of these studies is still ongoing and results are awaited as of 2022.

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7.2.5.1

Summary of evidence and recommendations for adjuvant therapy

Summary of evidence Adjuvant therapy does not improve survival after nephrectomy. In one single RCT, in selected high-risk patients, adjuvant sunitinib improved disease-free survival (DFS) but not overall survival (OS). Adjuvant sorafenib, pazopanib, everolimus, girentuximab or axitinib does not improve DFS or OS after nephrectomy. Adjuvant RCTs are ongoing to evaluate the benefit of adjuvant immunotherapy after nephrectomy in high-risk patients. Recommendations Do not offer adjuvant therapy with sorafenib, pazopanib, everolimus, girentuximab or axitinib. Do not offer adjuvant sunitinib following surgically resected high-risk clear-cell renal cell carcinoma.

7.3

LE 1b 1b 1b 1b

Strength rating Strong Weak

Advanced/metastatic RCC

7.3.1 Local therapy of advanced/metastatic RCC 7.3.1.1 Cytoreductive nephrectomy Tumour resection is potentially curative only if all tumour deposits are excised. This includes patients with the primary tumour in place and single- or oligometastatic resectable disease. For most patients with metastatic disease, cytoreductive nephrectomy (CN) is palliative and systemic treatments are necessary. In a combined analysis of two RCTs comparing CN+ IFN-based immunotherapy vs. IFN-based immunotherapy only, increased long-term survival was found in patients treated with CN [399]. However, IFN-based immunotherapy is no longer relevant in contemporary clinical practice. In order to investigate the role and sequence of CN in the era of targeted therapy, a structured literature assessment was performed to identify relevant RCTs and systematic reviews published between July 1st - June 30th 2019. Two RCTs [400, 401] and a narrative systematic review were identified [402]. The narrative systematic review included both RCTs and 10 non-randomised studies. CARMENA, a phase III non-inferiority RCT investigating immediate CN followed by sunitinib vs. sunitinib alone, showed that sunitinib alone was not inferior to CN followed by sunitinib with regard to OS [403]. The trial included 450 patients with metastatic ccRCC of intermediate- and MSKCC poor-risk of whom 226 were randomised to immediate CN followed by sunitinib and 224 to sunitinib alone. Patients in both arms had a median of two metastatic sites. Patients in both arms had a tumour burden of a median/mean of 140 mL of measurable disease by Response Evaluation Criteria In Solid Tumours (RECIST) 1.1, of which 80 mL accounted for the primary tumour. The study did not reach the full accrual of 576 patients and the Independent Data Monitoring Commission (IDMC) advised the trial steering committee to close the study. In an ITT analysis after a median follow-up of 50.9 months, median OS with CN was 13.9 months vs. 18.4 months with sunitinib alone (HR: 0.89, 95% CI: 0.71–1.10). This was found in both risk groups. For MSKCC intermediate-risk patients (n = 256) median OS was 19.0 months with CN and 23.4 months with sunitinib alone (HR: 0.92, 95% CI: 0.60–1.24) and for MSKCC poor risk (n = 193) 10.2 months and 13.3 months, respectively (HR: 0.86, 95% CI: 0.62–1.17). Non-inferiority was also found in two per-protocol analyses accounting for patients in the CN arm who either did not undergo surgery (n = 16) or did not receive sunitinib (n = 40), and patients in the sunitinib-only arm who did not receive the study drug (n = 11). Median PFS in the ITT population was 7.2 months with CN and 8.3 months with sunitinib alone (HR: 0.82, 95% CI: 0.67–1.00). The clinical benefit rate, defined as disease control beyond 12 weeks was 36.6% with CN and 47.9% with sunitinib alone (p = 0.022). Of note, 38 patients in the sunitinib-only arm required secondary CN due to acute symptoms or for complete or near-complete response. The median time from randomisation to secondary CN was 11.1 months. The randomised EORTC SURTIME study revealed that the sequence of CN and sunitinib did not affect PFS (HR: 0.88, 95% CI: 0.59–1.37, p = 0.569). The trial accrued poorly and therefore results are mainly exploratory. However, in secondary endpoint analysis a strong OS benefit was observed in favour of the deferred CN approach in the ITT population with a median OS of 32.4 (range 14.5–65.3) months in the deferred CN arm vs. 15.0 (9.3–29.5) months in the immediate CN arm (HR: 0.57, 95% CI: 0.34–0.95, p = 0.032). The deferred CN approach appears to select out patients with inherent resistance to systemic therapy [404]. This confirms previous findings from single-arm phase II studies [404, 405]. Moreover, deferred CN and surgery appear safe after sunitinib which supports the findings, with some caution, of the only available RCT.

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In patients with poor PS or IMDC poor risk, small primaries and high metastatic volume and/or a sarcomatoid tumour, CN is not recommended [406]. These data are confirmed by CARMENA [403] and upfront pre-surgical VEGFR-targeted therapy followed by CN seems to be beneficial [407]. Meanwhile first-line therapy recommendations for patients with their primary tumour in place have changed to immune checkpoint inhibitor combination therapy (see Section 7.4.2.4) with sunitinib and other VEGFRTKI monotherapies reserved for those who cannot tolerate immune checkpoint inhibitor (ICI) combination or have no access to these drugs. High level evidence regarding CN is not available for ICI combinations but up to 30% of patients with primary metastatic disease, treated with their tumour in place, were included in the pivotal ICI combination trials (Table 7.1). The subgroup HRs, where available, suggest better outcomes for the ICI combination compared to sunitinib monotherapy. In mRCC patients without a need for immediate drug treatment, a recent systematic review evaluating effects of CN demonstrated an OS advantage of CN [402]. These data were supported by a nation-wide registry study showing that patients selected for primary CN had a significant OS advantage across all age groups [408]. Table 7.1: Key trails on immune checkpoint inhibitor combinations for primary metastatic disease Trial

Drug combination

Number of patients Number and % of patients treated treated with the primary tumour in place with primary tumour in place (ICI combination vs. sunitinib) ICI combination

CheckMate 214 [409]

ipilimumab + nivolumab

Subgroup analyses (HR with 95% CIs)

sunitinib

PFS

OS

187/847 (22%)

84

103

NA

0.63 (0.42–0.94)

CheckMate 9ER cabozantinib + [410] nivolumab

196/651 (30.1%)

101

95

0.63 (0.43–0.92)

0.79 (0.48–1.29)

Javelin 101 [411]

axitinib + avelumab

179/886 (20.2%)

90

89

0.75 (0.48–1.65)

NA

KEYNOTE-426 [412]

axitinib + 143/861 (16.6%) pembrolizumab

73

70

0.68 (0.45–1.03)

0.57 (0.36–0.89)

CI = confidence interval; HR = hazard ratio; ICI = immune checkpoint inhibitor; NA = not available; PFS = profession-free survival; OS = overall survival. The results of CARMENA and SURTIME demonstrated that patients who require systemic therapy benefit from immediate drug treatment. While randomised trials to investigate deferred vs. no cytoreductive nephrectomy with ICI and ICI combinations are ongoing, the exploratory results from the ICI combination trials demonstrate that the respective IO+IO or TKI+IO combinations have a superior effect on the primary tumour and metastatic sites when compared to sunitinib alone (Table 7.1). In accordance with the CARMENA and SURTIME data this suggests that mRCC patients and IMDC intermediate- and poor-risk groups with their primary tumour in place should be treated with upfront IO-based combinations. In patients with a clinical response to IO-based combinations, a subsequent CN may be considered. 7.3.1.1.1 Embolisation of the primary tumour In patients unfit for surgery or with non-resectable disease, embolisation can control symptoms including visible haematuria or flank pain [264, 265, 368] (see recommendations Section 7.1.2.2.4). 7.3.1.1.2 Summary of evidence and recommendations for local therapy of advanced/metastatic RCC Summary of evidence Deferred CN with pre-surgical sunitinib in intermediate-risk patients with cc-mRCC shows a survival benefit in secondary endpoint analyses and selects out patients with inherent resistance to systemic therapy. Sunitinib alone is non-inferior compared to immediate CN followed by sunitinib in patients with MSKCC intermediate and poor risk who require systemic therapy with VEGFR-TKI. Cytoreductive nephrectomy in patients with simultaneous complete resection of a single metastasis or oligometastases may improve survival and delay systemic therapy.

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LE 2b

1a 3

39

Patients with MSKCC or IMDC poor risk (≥ 4 risk factors) do not benefit from local therapy. Patients with their primary tumour in place treated with ICI-based combination therapy have better PFS and OS in exploratory subgroup analyses compared to treatment with sunitinib. Recommendations Do not perform cytoreductive nephrectomy (CN) in MSKCC poor-risk patients. Do not perform immediate CN in intermediate-risk patients who have an asymptomatic synchronous primary tumour and require systemic therapy. Start systemic therapy without CN in intermediate-risk patients who have an asymptomatic synchronous primary tumour and require systemic therapy. Discuss delayed CN with patients who derive clinical benefit from systemic therapy. Perform immediate CN in patients with a good performance status who do not require systemic therapy. Perform immediate CN in patients with oligometastases when complete local treatment of the metastases can be achieved.

1a 2b

Strength rating Strong Weak Weak Weak Weak Weak

7.3.2 Local therapy of metastases in metastatic RCC A systematic review of the local treatment of metastases from RCC in any organ was undertaken [413]. Interventions included metastasectomy, various radiotherapy modalities, and no local treatment. The outcomes assessed were OS, CSS and PFS, local symptom control and adverse events. A risk-of-bias assessment was conducted [414]. Of the 2,235 studies identified only sixteen non-randomised comparative studies were included. Eight studies reported on local therapies of RCC-metastases in various organs [415-422]. This included metastases to any single organ or multiple organs. Three studies reported on local therapies of RCC metastases in bone, including the spine [423-425], two in the brain [426, 427] and one each in the liver [428] lung [429] and pancreas [430]. Three studies were published as abstracts only [418, 420, 429]. Data were too heterogeneous to meta-analyse. There was considerable variation in the type and distribution of systemic therapies (cytokines and VEGF-inhibitors) and in reporting the results. 7.3.2.1 Complete versus no/incomplete metastasectomy A systematic review, including only 8 studies, compared complete vs. no and/or incomplete metastasectomy of RCC metastases in various organs [415-422]. In one study complete resection was achieved in only 45% of the metastasectomy cohort, which was compared with no metastasectomy [422]. Non-surgical modalities were not applied. Six studies [416-418, 420-422] reported a significantly longer median OS or CSS following complete metastasectomy (the median value for OS or CSS was 40.75 months, range 23–122 months) compared with incomplete and/or no metastasectomy (the median value for OS or CSS was 14.8 months, range 8.4–55.5 months). Of the two remaining studies, one [415] showed no significant difference in CSS between complete and no metastasectomy, and one [419] reported a longer median OS for metastasectomy albeit no p-value was provided. Three studies reported on treatment of RCC metastases in the lung [429], liver [428], and pancreas [430], respectively. The lung study reported a significantly higher median OS for metastasectomy vs. medical therapy only for both targeted therapy and immunotherapy. Similarly, the liver and pancreas study reported a significantly higher median OS and 5-year OS for metastasectomy vs. no metastasectomy. 7.3.2.2 Local therapies for RCC bone metastases Of the three studies identified, one compared single-dose image-guided radiotherapy (IGRT) with hypofractionated IGRT in patients with RCC bone metastases [425]. Single-dose IGRT (≥ 24 Gy) had a significantly better 3-year actuarial local PFS rate, also shown by Cox regression analysis. Another study compared metastasectomy/curettage and local stabilisation with no surgery of solitary RCC bone metastases in various locations [423]. A significantly higher 5-year CSS rate was observed in the intervention group. After adjusting for prior nephrectomy, gender and age, multi-variable analysis still favoured metastasectomy/ curettage and stabilisation. A third study compared the efficacy and durability of pain relief between singledose stereotactic body radiotherapy (SBRT) and conventional radiotherapy in patients with RCC bone metastases to the spine [424]. Pain, ORR, time-to-pain relief and duration of pain relief were similar. 7.3.2.3 Local therapies for RCC brain metastases Two studies on RCC brain metastases were included. A three-armed study compared stereotactic radiosurgery (SRS) vs. whole brain radiotherapy (WBRT) vs. SRS and WBRT [426]. Each group was further subdivided into

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recursive partitioning analysis (RPA) classes I to III (I favourable, II moderate and III poor patient status). Twoyear OS and intra-cerebral control were equivalent in patients treated with SRS alone and SRS plus WBRT. Both treatments were superior to WBRT alone in the general study population and in the RPA subgroup analyses. A comparison of SRS vs. SRS and WBRT in a subgroup analysis of RPA class I showed significantly better 2-year OS and intra-cerebral control for SRS plus WBRT based on only three participants. The other study compared fractionated stereotactic radiotherapy (FSRT) with metastasectomy and conventional radiotherapy or conventional radiotherapy alone [427]. Several patients in all groups underwent alternative surgical and non-surgical treatments after initial treatment. One-, two- and 3-year survival rates were higher but not significantly so for FSRT as for metastasectomy and conventional radiotherapy, or conventional radiotherapy alone. Fractionated stereotactic radiotherapy did not result in a significantly better 2-year local control rate compared with metastasectomy plus conventional radiotherapy. 7.3.2.4 Embolisation of metastases Embolisation prior to resection of hypervascular bone or spinal metastases can reduce intra-operative blood loss [431]. In selected patients with painful bone or paravertebral metastases, embolisation can relieve symptoms [432] (see recommendation Section 7.1.2.2.4). 7.3.2.5 Adjuvant treatment in cM0 patients after metastasectomy Patients after metastasectomy and no evidence of disease (cM0) have a high risk of relapse. Recent attempts to reduce RFS by offering adjuvant TKI treatment after metastasectomy did not demonstrate an improvement in RFS. In a recent phase II trial 129 patients were randomised to either pazopanib 800 mg daily vs. placebo for 52 weeks. The primary study endpoint of a 42% DFS improvement from 25% to 45% at three years was not met. Hazard ratio for DFS in pazopanib vs. placebo-treated patients was 0.85 (0.55–1.31), p = 0.47 [433]. A second phase II trial randomised 69 ccRCC patients after metastasectomy and no evidence of disease to either sorafenib (400 mg twice daily) or observation. The study was terminated early due to slow accrual and the availability of new agents and multimodal treatment options, including surgery or a locoregional approach. The primary endpoint of RFS was not reached with a RFS of 21 months in the sorafenib arms vs. 37 months in the observation arm (p = 0.404) [434]. 7.3.2.6

Summary of evidence and recommendations for local therapy of metastases in metastatic RCC

Summary of evidence All studies included in the Panel systematic review were retrospective non-randomised comparative studies, resulting in a high risk of bias associated with non-randomisation, attrition, and selective reporting. With the exception of brain and possibly bone metastases, metastasectomy remains by default the only local treatment for most sites. Retrospective comparative studies consistently point towards a benefit of complete metastasectomy in mRCC patients in terms of overall survival, cancer-specific survival and delay of systemic therapy. Radiotherapy to bone and brain metastases from RCC can induce significant relief from local symptoms (e.g. pain). Tyrosine kinase inhibitors treatment after metastasectomy in patients with no evidence of disease did not improve RFS when compared to placebo or observation. Recommendations To control local symptoms, offer ablative therapy, including metastasectomy, to patients with metastatic disease and favourable disease factors and in whom complete resection is achievable. Offer stereotactic radiotherapy for clinically relevant bone or brain metastases for local control and symptom relief. Do not offer tyrosine kinase inhibitor treatment to mRCC patients after metastasectomy and no evidence of disease.

7.4

LE 3

3 3 3 1b

Strength rating Weak

Weak Strong

Systemic therapy for advanced/metastatic RCC

7.4.1 Chemotherapy Chemotherapy has proven to be generally ineffective in the treatment of RCC but can be offered in rare patients, with the exception of collecting duct and medullary carcinoma [435].

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7.4.1.1

Recommendation for systemic therapy in advanced/metastatic RCC

Recommendation Do not offer chemotherapy to patients with metastatic renal cell carcinoma.

Strength rating Strong

7.4.2 Immunotherapy 7.4.2.1 IFN-α monotherapy and combined with bevacizumab All studies comparing targeted drugs to IFN-α monotherapy therapy showed superiority for sunitinib, bevacizumab plus IFN-α, and temsirolimus [436-439]. Interferon-α has been superseded by targeted therapy in cc-mRCC. Table 7.2: The Metastatic Renal Cancer Database Consortium (IMDC) risk model [440]* Risk factors** Karnofsky performance status Time from diagnosis to treatment Haemoglobin Corrected serum calcium Absolute neutrophil count (neutrophilia) Platelets (thrombocytosis)

Cut-off point used < 80% < 12 months < Lower limit of laboratory reference range > 10.0 mg/dL (2.4 mmol/L) > upper limit of normal > upper limit of normal

*The MSKCC (Motzer) criteria are also widely used in this setting [225]. **Favourable (low) risk, no risk factors; intermediate risk, one or two risk factors; poor (high) risk, three to six risk factors. 7.4.2.2 Interleukin-2 Interleukin-2 has been used to treat mRCC since 1985 with response rates ranging from 7–27% [439, 441, 442]. Complete and durable responses have been achieved with high-dose bolus IL-2, however, this can be achieved at less toxicity with immune checkpoint inhibitor combination therapy and IL-2 is no longer widely used. 7.4.2.3 Immune checkpoint blockade 7.4.2.3.1 Immuno-oncology monotherapy Immune checkpoint blockade with monoclonal antibodies targets and blocks the inhibitory T-cell receptor PD-1 or cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)-signalling to restore tumour-specific T-cell immunity [443]. Immune checkpoint inhibitor monotherapy has been investigated as second- and third-line therapy. A phase III trial of nivolumab vs. everolimus after one or two lines of VEGF-targeted therapy for mRCC with a clear cell component (CheckMate 025, NCT01668784) reported a longer OS, better QoL and fewer grade 3 or 4 adverse events with nivolumab than with everolimus [444]. Nivolumab has superior OS to everolimus (HR: 0.73, 95% CI: 0.57–0.93, p < 0.002) in VEGF-refractory RCC with a median OS of 25 months for nivolumab and 19.6 months for everolimus with a 5-year OS probability of 26% vs. 18% [445] (LE: 1b). Patients who had failed multiple lines of VEGF-targeted therapy were included in this trial making the results broadly applicable. The trial included 15% MSKCC poor-risk patients. There was no PFS advantage with nivolumab despite the OS advantage. Progression-free survival does not appear to be a reliable surrogate of outcome for PD-1 therapy in RCC. Currently PD-L1 biomarkers are not used to select patients for this therapy. There are no RCTs supporting the use of single-agent immune checkpoint blockade in treatment-naive patients. Randomised phase II data for atezolizumab vs. sunitinib showed a HR of 1.19 (95% CI: 0.82–1.71) which did not justify further assessment of atezolizumab as single agent as first-line treatment option in this group of patients, despite high complete response rates in the biomarker-positive population [446]. Single-arm phase II data for pembrolizumab from the KEYNOTE-427 trial show high response rates of 38% (up to 50% in PD-L1+ patients), but a PFS of 8.7 months (95% CI: 6.7–12.2) [447]. Based on these results and in the absence of randomised phase III data, single-agent checkpoint inhibitor therapy is not recommended as an alternative in a first-line therapy setting. 7.4.2.4 Immunotherapy/combination therapy The phase III trial CheckMate 214 (NCT 02231749) showed a superiority of nivolumab and ipilimumab over sunitinib. The primary endpoint population focused on the IMDC intermediate- and poor-risk population where the combination demonstrated an OS benefit (HR: 0.63, 95% CI: 0.44–0.89) which led to regulatory approval [409] and a paradigm shift in the treatment of mRCC [1]. Results from CheckMate 214 further established that

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the combination of ipilimumab and nivolumab was associated with higher response rates (RR) (39% in the ITT population), complete response rates (8% in the ITT population [central radiology review]) and duration of response compared to sunitinib. Progression-free survival did not achieve the pre-defined endpoint. The exploratory analysis of OS data in the PD-L1-positive population was 0.45 (95% CI: 0.29–0.41). A recent update with 48-month data shows ongoing benefits for the immune combination with independently assessed complete response rates of 10% and a HR for OS in the IMDC intermediate- and poor-risk group of 0.65 (0.54–0.78). The 48-months OS propability was 50% for ipilimumab plus nivolumab vs. 39% for sunitinib, respectively [448]. The IMDC good-risk group continues to perform better with sunitinib although this appears less marked than in earlier analyses (HR for OS: 0.93 [95% CI: 0.62–1.40]) [448]. Nivolumab plus ipilimumab was associated with 15% grade 3-5 toxicity including 1.5% treatment-related deaths. It should therefore be administered in centres with experience of immune combination therapy and appropriate supportive care within the context of a multidisciplinary team (LE: 4). PD-L1 biomarker is currently not used to select patients for therapy. The frequency of steroid use has generated controversy and further analysis, as well as real world data, are required. For these reasons the Panel continues to recommend ipilimumab and nivolumab in the intermediate- and poor-risk population. The KEYNOTE-426 trial (NCT02853331 reported results for the combination of axitinib plus pembrolizumab vs. sunitinib in 861 treatment-naive cc-mRCC patients [449]. Overall survival and PFS assessed by central independent review in the ITT population were the co-primary endpoints. Response rates and assessment in the PD-L1-positive patient population were secondary endpoints. With a median follow-up of 12.8 months, at first interim analysis both primary endpoints were reached, The median PFS in the pembrolizumab plus axitinib arm was 15.1 months vs. 11.1 in the sunitinib arm (HR: 0.69, 95% CI: 0.57–0.84, p < 0.001). Median OS has not been reached in either arm, but the risk of death was 47% lower in the axitinib plus pembrolizumab arm when compared to the sunitinib arm (OS HR: 0.53, 95% CI: 0.38–0.74, p < 0.0001). Response rates were also higher in the experimental arm (59.3% vs. 35.7%). Efficacy occurred irrespective of IMDC group and PD-L1 status. Treatment-related AEs (≥ grade 3) occurred in 63% of patients receiving axitinib and pembrolizumab vs. 58% of patients receiving sunitinib. Treatment-related deaths occurred in approximately 1% in both arms. A recent update of KEYNOTE-426 with a minimum follow-up of 23.4 months (median 30.6 months) demonstrated an ongoing OS benefit for axitinib plus pembrolizumab in the ITT population (HR: 0.68, 95% CI: 0.55–0.85, p < 0.001) and PFS benefit (HR: 0.71, 95% CI: 0.60–0.84, p < 0.0001 which was across all IMDC subgoups for PFS, while OS was similar between axitinib plus pembrolizumab vs. sunitinib in the favourable subgroup with an OS benefit in the IMDC intermediate- and poor-risk groups. The complete response rate by independent review was 9% in the pembrolizumab plus axitinib arm and 3% in the sunitinib arm [450]. The phase III CheckMate 9ER trial randomised 651 patients to nivolumab plus cabozantinib (n = 323) or vs. sunitinib (n = 328) in treatment-naive cc-mRCC patients. The primary endpoint of PFS assessed by central independent review in the ITT population was siginifcantly prolonged for nivolumab plus cabozantinib (16.6 months) vs. sunitinib (8.3 months, HR: 0.51, 95% CI: 0.41–0.64, p < 0.0001). The nivolumab/cabozantinib combination also demonstrated a significant OS benefit in the secondary endpoint compared with sunitinib (HR: 0.60, CI: 0.40–0.89, p = 0.0010) after a median follow-up of 18.1 months. The independantly assessed ORR was 55.7% vs. 27.1% with a complete response rate of 8% for nivolumab plus cabozantinib vs. 4.6% with sunitinib. The efficacy was observed independent of IMDC group and PD-L1 status. Treatment-related AEs (≥ grade 3) occurred in 61% of patients receiving cabozantinib and nivolumab vs. 51% of patients receiving sunitinib. Treatment-related deaths occurred in one patient in the nivolumab/cabozantinib arm and in two patients in the sunitinib arm. Recently, the randomised phase III trial CLEAR (Lenvatinib/Everolimus or Lenvatinib/Pembrolizumab Versus Sunitinib Alone as Treatment of Advanced Renal Cell Carcinoma) was published [451]. CLEAR randomised a total of 1,069 patients (in a 1:1:1 ratio) to lenvatinib plus pembrolizumab (n = 355) vs. lenvatinib plus everolimus (n = 357) vs. sunitinib (n = 357). The trial reached its primary endpoint of independently assessed PFS at a median of 23.9 vs. 9.2 months, for lenvatinib plus pembrolizumab vs. sunitinib, respectively (HR: 0.39, 95% CI: 0.32–0.49, p < 0.001). Overall survival siginificantly improved with lenvatinib plus pembrolizumab vs. sunitinib (HR: 0.66, 95% CI: 0.49–0.88, p = 0.005). Objective response for lenvatinib plus pembrolizumab was 71% with 16% of the patients having a complete remission. Efficacy was observed across all IMDC risk groups, independently of PD-L1 status. Treatment-related AEs of grade 3 and higher with lenvatinib plus pembrolizumab were 72%. Treatment-related death occurred in four patients in the lenvatinib plus pembrolizumab arm and in one patient in the sunitinib arm.

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The JAVELIN trial investigated 886 patients in a phase III RCT of avelumab plus axitinib vs. sunitinib [411]. The trial met one of its co-primary endpoints (PFS in the PD-L1-positive population at first interim analysis [median follow up 11.5 months]). Hazard ratios for PFS and OS in the ITT population were 0.69 (95% CI: 0.56–0.84) and 0.78 (95% CI: 0.55–1.08), respectively. The same applies to the atezolizumab/bevacizumab combination which also achieved a PFS advantage over sunitinib in the PD-L1-positive population at interim analysis and ITT (HR: 0.74, 95% CI: 0.57–0.96), but has not yet shown a significant OS advantage (HR: 0.81, 95% CI: 0.63–1.03) [452]. Final OS results are awaited and the combination cannot currently be recommended. Table 7.3: First line immune checkpoint inhibitor combination trials for clear-cell RCC Cross trial comparison is not recommended and should occur with caution Study

OS (mo) Median (95% CI) HR

Experimental arm

Primary endpoint

Risk groups

PFS (mo) Median (95% CI) HR

KEYNOTE-426 861 NCT02853331 Median follow-up 30.6 months [449, 450]

Pembrolizumab 200 mg. IV Q3W plus axitinib 5 mg. PO BID vs. sunitinib 50 mg PO QD 4/2 wk

PFS and OS in the ITT by BICR

IMDC FAV 31% IMD 56% POOR 13%

(ITT) (ITT) PEMBRO + AXI: NR PEMBRO + AXI: SUN: 35.7 (33.3-NE) 15.4 (12.7-18.9) SUN: 11.1 (9.1-12.5)

JAVELIN 101 NCT02684006 Median follow-up 19 months [411, 453]

886

Avelumab 10 mg/ kg IV Q2W plus axitinib, 5 mg PO BID vs. sunitinib 50 mg PO QD 4/2 wk

PFS in the PD-L1+ population and OS in the ITT by BICR

IMDC FAV 22% IMD 62% POOR 16%

Immotion 151 NCT02420821 Median follow-up 24 months [452]

915

Atezolizumab 1200 mg fixed dose IV plus bevacizumab 15 mg/kg IV on days 1 and 22 of each 42-day cycle vs. sunitinib 50 mg. PO QD 4/2 wk

PFS in the PD-L1+ population and OS in the ITT by IR

IMDC (PD-L1+) Not ATEZO + BEV: determined 11.2 (8.9-15.0) SUN: 7.7 (6.8-9.7) MSKCC FAV 20% HR: 0.74 IMD 69% (95% CI: 0.57, 0.96) POOR 12% p = 0.0217

(ITT) ATEZO + BEV: 33.6 (29.0-NE) SUN: 34.9 (27.8-NE)

Checkmate 214 NCT02231749 Median follow-up 48 months [409, 448]

1096 Nivolumab 3 mg/kg plus ipilimumab 1 mg/ kg IV Q3W for 4 doses then nivolumab 3 mg/ kg IV Q2W vs. sunitinib 50 mg. PO QD 4/2 wk

PFS and OS in the IMDC inter­ mediate and poor population by BICR

IMDC (IMDC IMD/poor) FAV 23% NIVO + IPI: IMD 61% 11.2 (8.4-16.1) POOR 17% SUN: 8.3 (7.0-10.8)

(IMDC IMD/poor) NIVO + IPI: 48.1 (35.6-NE) SUN: 26.6 (22.1-33.5)

CheckMate 9ER NCT03141177 Median follow-up 18.1 months [410]

651

IMDC (ITT) PFS in 22% NIVO + CABO: the ITT by FAV IMD 58% 16.6 (12.5-24.9) BICR POOR 20% SUN: 8.3 (7.0-9.7)

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N

Nivolumab 240 mg fixed dose IV every 2 wk plus cabozantinib 40 mg PO daily vs. sunitinib 50 mg PO QD 4/2 wk

MSKCC HR: 0.68 HR: 0.71 Not (95% CI: 0.60, 0.84) (95% CI: 0.55-0.85) determined p < 0.0001 p = 0.0003 (PD-L1+) AVE + AXI: 13.8 (10.1-20.7) SUN: 7.0 (5.7-9.6)

(PD-L1+) AVE + AXI: NR SUN: 28.6 (27.4-NE)

HR: 0.83 MSKCC (95% CI: 0.60-1.15) HR: 0.62 FAV 23% (95% CI: 0.49, 0.78) p = 0.1301 IMD 66% p < 0.0001 POOR 12%

HR: 0.93 (95% CI: 0.76-1.14) p 0.4751

MSKCC HR: 0.74 Not (95% CI: 0.62, 0.88) HR: 0.65 determined (0.54-0.78) p < 0.0001 (ITT) NIVO + CABO: NR (NE) SUN: NR (22.6-NE)

MSKCC HR: 0.51 HR: 0.60 Not (95% CI: 0.41-0.64) (98.9% CI: 0.40-0.89) determined p < 0.0001 p = 0.0010

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2021

CLEAR NCT02811861 Median follow-up 26.6 months [451]

712

Pembrolizumab 200 mg IV Q3W plus lenvatinib 20 mg PO QD vs. sunitinib 50 mg PO QD 4/2 wk

IMDC (ITT) PFS in the ITT by FAV 31% PEMBRO + LEN: IMD 59% 23.9 (20.8-27.7) BIRC POOR 9% SUN: 9.2 (6.0-11.0) NE 1% MSKCC HR: 0.39 FAV 27% (95% CI: 0.32-0.49) IMD 64% p > 0.001 POOR 9%

(ITT) PEMBRO + LEN: NR (33.6-NE) SUN: NR (NE-NE) HR: 0.66 (95% CI: 0.49-0.88) p = 0.005

ATEZO = atezolizumab; AVE = avelumab; AXI = axitinib; BEV = bevacizumab; BICR = blinded independent central review; BID = twice a day; CABO = cabozantinib; CI = confidence interval; FAV = favourable; R = hazard ratio; IPI = ipilimumab; IMD = intermediate; IMDC = Metastatic Renal Cancer Database Consortium; IR = investigator review; ITT = intention-to-treat; IV = intravenous; LEN = lenvatinib; mo = months; MSKCC = Memorial Sloan Kettering Cancer Center; NE = non-estimable; NR = not reached; NIVO = nivolumab; OS = overall survival; PEMBRO = pembrolizumab; PFS = profession-free survival; PO = by mouth; BID = twice a day; QD = once a day; Q2W = every 2 weeks; Q3W = every 3 weeks; SUN = sunitinib; wk = weeks. Patients who stop nivolumab plus ipilimumab because of toxicity require expert guidance and support from a multidisciplinary team before re-challenge can occur (LE: 1). Patients who do not receive the full four doses of ipilimumab due to toxicity should continue on single-agent nivolumab, where safe and feasible (LE: 4). Treatment past progression with nivolumab plus ipilimumab can be justified but requires close scrutiny and the support of an expert multidisciplinary team [454, 455] (LE: 1). Patients who stop TKI and IO due to immune-related toxicity can receive single-agent TKI once the adverse event has resolved (LE: 1). Adverse event management, including transaminitis and diarrhoea, require particular attention as both agents may be causative. Expert advice should be sought on re-challenge of immune checkpoint inhibitors after significant toxicity (LE: 4). Treatment past progression on axitinib plus pembrolizumab or nivolumab plus cabozantinib requires careful consideration as it is biologically distinct from treatment past progression on ipilimumab and nivolumab. Generally, the Panel is of the opinion that nivolumab plus ipilimumab, pembrolizumab plus axitinib and nivolumab plus cabozantinib should be administered in centres with experience of immune combination therapy and appropriate supportive care within the context of a multidisciplinary team (LE: 4). 7.4.2.5

Summary of evidence and recommendations for immunotherapy in metastatic RCC

Summary of evidence Interferon-α monotherapy is inferior to VEGF-targeted therapy or mTOR inhibition in mRCC. Nivolumab leads to superior OS compared to everolimus in patients failing one or two lines of VEGFtargeted therapy. The combination of nivolumab and ipilimumab in treatment-naive patients with clear-cell-mRCC (cc-mRCC) of IMDC intermediate- and poor-risk demonstrated overall survival (OS) and objective response rate (ORR) benefits compared to sunitinib. The combination of pembrolizumab plus axitinib, lenvatinib plus pembrolizumab and nivolumab plus cabozantinib in treatment-naive patients with cc-mRCC across all IMDC risk group demonstrated PFS, OS and ORR benefits compared to sunitinib. Currently, PD-L1 expression is not used for patient selection. Axitinib, cabozantinib or lenvatinib can be continued if immune-related adverse events result in cessation of axitinib plus pembrolizumab, cabozantinib plus nivolumab or lenvatinib plus pembrolizumab. Re-challenge with immunotherapy requires expert support. Patients who do not receive the full 4 doses of ipilimumab due to toxicity should continue on singleagent nivolumab, where safe and feasible. Re-challenge with combination therapy requires expert support. Treatment past progression can be justified but requires close scrutiny and the support of an expert multidisciplinary team. Nivolumab plus ipilimumab, pembrolizumab plus axitinib, nivolumab plus cabozantinib and lenvatinib plus pembrolizumab should be administered in centres with experience of immune combination therapy and appropriate supportive care within the context of a multidisciplinary team.

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LE 1b 1b 1b

1b

2b 4

4

1b 4

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The combination of nivolumab plus ipilimumab in the IMDC intermediate- and poor-risk population of 2b treatment-naive patients with cc-mRCC leads to superior survival compared to sunitinib while OS was higher in IMDC good-risk patients with sunitinib. Nivolumab plus ipilimumab was associated with 15% grade 3-5 toxicity and 1.5% treatment-related 1b deaths. Recommendations Offer pembrolizumab plus axitinib, lenvatinib plus pembrolizumab or nivolumab plus cabozantinib to treatment-naive patients in clear-cell metastatic renal cell carcinoma (cc-mRCC). Offer ipilimumab plus nivolumab to treatment-naive patients with IMDC intermediate- and poor-risk cc-mRCC. Administer nivolumab plus ipilimumab, pembrolizumab plus axitinib, lenvatinib plus pembrolizumab and nivolumab and cabozantinib in centres with experience of immune combination therapy and appropriate supportive care within the context of a multidisciplinary team. Patients who do not receive the full 4 doses of ipilimumab due to toxicity should continue on single-agent nivolumab, where safe and feasible. Offer axitinib, cabozantinib or lenvatinib as subsequent treatment to patients who experience treatment-limiting immune-related adverse events after treatment with the combination of axitinib plus pembrolizumab, cabozantinib plus nivolumab or lenvatinib plus pembrolizumab. Treatment past progression can be justified but requires close scrutiny and the support of an expert multidisciplinary team. Do not re-challenge patients who stopped immune checkpoint inhibitors because of toxicity without expert guidance and support from a multidisciplinary team. Offer sunitinib or pazopanib to treatment-naive patients with IMDC favourable-, intermediate-, and poor-risk cc-mRCC who cannot receive or tolerate immune checkpoint inhibition. Offer cabozantinib to treatment-naive patients with IMDC intermediate- and poor-risk cc-mRCC who cannot receive or tolerate immune checkpoint inhibition. a

Strength rating Strong

Strong Weak

Weak Weak

Weak Strong Strong Stronga

While this is based on a randomised phase II trial, cabozantinib (weak) looks at least as good as sunitinib in this population. This justified the same recommendation under exceptional circumstances.

7.4.3 Targeted therapies In sporadic ccRCC, hypoxia-inducible factor (HIF) accumulation due to VHL-inactivation results in overexpression of VEGF and platelet-derived growth factor (PDGF), which promote neo-angiogenesis [456-458]. This process substantially contributes to the development and progression of RCC. Several targeting drugs for the treatment of mRCC are approved in both the USA and Europe. Most published trials have selected for clear-cell carcinoma subtypes, thus no robust evidencebased recommendations can be given for non-ccRCC subtypes. In major trials leading to registration of the approved targeted agents, patients were stratified according to the IMDC risk model (Table 7.2) [227]. Table 7.4: M  edian OS and percentage of patients surviving two years treated in the era of targeted therapy per IMDC risk group*,** IMDC Model Favourable Intermediate Poor

Patients** n 157 440 252

% 18 52 30

Median OS* (months) 43.2 22.5 7.8

2-yr OS (95% CI)** 75% (65–82%) 53% (46–59%) 7% (2–16%)

* Based on [227]; ** based on [440]. CI = confidence interval; IMDC = Metastatic Renal Cancer Database Consortium; n = number of patients; OS = overall survival; yr = year.

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7.4.3.1 Tyrosine kinase inhibitors 7.4.3.1.1 Sorafenib Sorafenib is an oral multi-kinase inhibitor. A trial compared sorafenib and placebo after failure of prior systemic immunotherapy or in patients unfit for immunotherapy. Sorafenib improved PFS (HR: 0.44, 95% CI: 0.35–0.55, p < 0.01) [459]. Overall survival improved in patients initially assigned to placebo who were censored at crossover [460]. In patients with previously untreated mRCC sorafenib was not superior to IFN-α (phase II study). A number of studies have used sorafenib as the control arm in sunitinib-refractory disease vs. axitinib, dovitinib or temsirolimus. None showed superior survival for the study drug compared to sorafenib. 7.4.3.1.2 Sunitinib Sunitinib is an oral TKI inhibitor and has anti-tumour and anti-angiogenic activity. First-line monotherapy with sunitinib demonstrated significantly longer PFS compared with IFN-α. Overall survival was greater in patients treated with sunitinib (26.4 months) vs. IFN-α (21.8 months) despite crossover [461]. In the EFFECT trial, sunitinib 50 mg/day (4 weeks on/2 weeks off) was compared with continuous uninterrupted sunitinib 37.5 mg/day in patients with cc-mRCC [462]. No significant differences in OS were seen (23.1 vs. 23.5 months, p = 0.615). Toxicity was comparable in both arms. Because of the non-significant, but numerically longer time to progression with the standard 50 mg dosage, the authors recommended using this regimen. Alternate scheduling of sunitinib (2 weeks on/one week off) is being used to manage toxicity, but robust data to support its use is lacking [463, 464]. 7.4.3.1.3 Pazopanib Pazopanib is an oral angiogenesis inhibitor. In a trial of pazopanib vs. placebo in treatment-naive mRCC patients and cytokine-treated patients, a significant improvement in PFS and tumour response was observed [465]. A non-inferiority trial comparing pazopanib with sunitinib (COMPARZ) established pazopanib as an alternative to sunitinib. It showed that pazopanib was not associated with significantly worse PFS or OS compared to sunitinib. The two drugs had different toxicity profiles, and QoL was better with pazopanib [466]. In another patient-preference study (PISCES), patients preferred pazopanib to sunitinib (70% vs. 22%, p < 0.05) due to symptomatic toxicity [467]. Both studies were limited in that intermittent therapy (sunitinib) was compared with continuous therapy (pazopanib). 7.4.3.1.4 Axitinib Axitinib is an oral selective second-generation inhibitor of VEGFR-1, -2, and -3. Axitinib was first evaluated as second-line treatment. In the AXIS trial, axitinib was compared to sorafenib in patients who had previously failed cytokine treatment or targeted agents (mainly sunitinib) [468]. The overall median PFS was greater for axitinib than sorafenib. Axitinib was associated with a greater PFS than sorafenib (4.8 vs. 3.4 months) after progression on sunitinib. Axitinib showed grade 3 diarrhoea in 11%, hypertension in 16%, and fatigue in 11% of patients. Final analysis of OS showed no significant differences between axitinib or sorafenib [469, 470]. In a randomised phase III trial of axitinib vs. sorafenib in first-line treatment-naive cc-mRCC, a significant difference in median PFS between the treatment groups was not demonstrated, although the study was underpowered, raising the possibility of a type II error [471]. As a result of this study, axitinib is not approved for first-line therapy. 7.4.3.1.5 Cabozantinib Cabozantinib is an oral inhibitor of tyrosine kinase, including MET, VEGF and AXL. Cabozantinib was investigated in a phase I study in patients resistant to VEGFR and mTOR inhibitors demonstrating objective responses and disease control [197]. Based on these results an RCT investigated cabozantinib vs. everolimus in patients with ccRCC failing one or more VEGF-targeted therapies (METEOR) [472, 473]. Cabozantinib delayed PFS compared to everolimus in VEGF-targeted therapy refractory disease (HR: 0.58, 95% CI: 0.45–0.75) [472] (LE: 1b). The median OS was 21.4 months (95% CI: 18.7 to not estimable) with cabozantinib and 16.5 months (95% CI: 14.7–18.8) with everolimus in VEGF-resistant RCC. The HR for death was 0.66 (95% CI: 0.53–0.83, p = 0.0003) [473]. Grade 3 or 4 adverse events were reported in 74% with cabozantinib and 65% with everolimus. Adverse events were managed with dose reductions; doses were reduced in 60% of the patients who received cabozantinib. The Alliance A031203 CABOSUN randomised phase II trial comparing cabozatinib and sunitinib in first-line in 157 intermediate- and poor-risk patients favoured cabozantinib for RR and PFS, but not OS [474, 475]. Cabozantinib significantly increased median PFS (8.2 vs. 5.6 months, adjusted HR: 0.66, 95% CI: 0.46 to 0.95; one-sided p = 0.012). Objective response rate was 46% (95% CI: 34–57) for cabozantinib vs. 18% (95% CI: 10–28) for sunitinib. All-causality grade 3 or 4 adverse events were similar for cabozantinib and sunitinib. No difference in OS was seen. Due to limitations of the statistical analyses within this trial the evidence is inferior over existing choices. RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2021

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7.4.3.1.6 Lenvatinib Lenvatinib is an oral multi-target TKI of VEGFR1, VEGFR2, and VEGFR3, with inhibitory activity against fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3, and FGFR4), platelet growth factor receptor (PDGFR-α), re-arranged during transfection (RET) and receptor for stem cell factor (KIT). It has recently been investigated in a randomised phase II study in combination with everolimus vs. lenvatinib or everolimus alone (see Section 7.4.6.1.1 for discussion of results) [476]. 7.4.3.1.7 Tivozanib Tivozanib is a potent and selective TKI of VEGFR1, VEGFR2, and VEGFR3 and was compared in two phase III trials with sorafenib in patients with mRCC [477, 478]. Tivozanib was approved by the EMA in front-line mRCC. While it was associated with a PFS advantage in both studies, no OS advantage was seen. In view of the choice of sorafenib as the control arm in the front-line trial, the Panel considers there is too much uncertainty, and too many attractive alternatives, to support its use in this front-line setting. 7.4.4 Monoclonal antibody against circulating VEGF 7.4.4.1 Bevacizumab monotherapy and bevacizumab plus IFN-α Bevacizumab is a humanised monoclonal antibody. The double-blind AVOREN study compared bevacizumab plus IFN-α with IFN-α monotherapy in mRCC. Overall response was higher in the bevacizumab plus IFN-α group. Median PFS increased from 5.4 months with IFN-α to 10.2 months with bevacizumab plus IFN-α. No benefit was seen in MSKCC poor-risk patients. Median OS in this trial, which allowed crossover after progression, was not greater in the bevacizumab/IFN-α group (23.3 vs. 21.3 months) [479]. An open-label trial (CALGB 90206) of bevacizumab plus IFN-α vs. IFN-α showed a higher median PFS for the combination group [480, 481]. Objective response rate was also higher in the combination group. Overall toxicity was greater for bevacizumab plus IFN-α, with significantly more grade 3 hypertension, anorexia, fatigue, and proteinuria. Bevacizumab, alone, or in combinations, is not widely recommended or used in mRCC due to more attractive alternatives. 7.4.5 mTOR inhibitors 7.4.5.1 Temsirolimus Temsirolimus is a specific inhibitor of mTOR [482]. Its use has been superseded as front-line treatment option. 7.4.5.2 Everolimus Everolimus is an oral mTOR inhibitor, which is established in the treatment of VEGF-refractory disease. The RECORD-1 study compared everolimus plus best supportive care (BSC) vs. placebo plus BSC in patients with previously failed anti-VEGFR treatment (or previously intolerant of VEGF-targeted therapy) [483]. The data showed a median PFS of 4 vs. 1.9 months for everolimus and placebo, respectively [483]. The Panel consider, even in the absence of conclusive data, that everolimus may present a therapeutic option in patients who were intolerant to, or previously failed, immune- and VEGFR-targeted therapies (LE: 4). Recent phase II data suggest adding lenvatinib is attractive. 7.4.6 Therapeutic strategies 7.4.6.1 Therapy for treatment-naïve patients with clear-cell metastatic RCC The combination of pembrolizumab plus axitinib as well as nivolumab plus cabozantinib and lenvatinib plus pembrolizumab is the standard of care in all IMDC-risk patients and ipilimumab plus nivolumab in IMDC intermediate- and poor-risk patients (Figure 7.1). Therefore, the role of VEGFR-TKIs alone in front-line mRCC has been superseded. Sunitinib, pazopanib, and cabozantinib (IMDC intermediate- and poor-risk disease), remain alternative treatment options for patients who cannot receive or tolerate immune checkpoint inhibition in this setting (Figure 7.1). 7.4.6.1.1 Sequencing systemic therapy in clear-cell metastatic RCC The sequencing of targeted therapies is established in mRCC and maximises outcomes [444, 472, 476]. Pembrolizumab plus axitinib, nivolumab plus cabozantinib, lenvatinib plus pembrolizumab and nivolumab plus ipilimumab are the new standard of care in front-line therapy. The impact of front-line immune checkpoint inhibition on subsequent therapies is unclear. Randomised data on patients with disease refractory to either nivolumab plus ipilimumab or TKI plus IO in a first-line setting are lacking, and available cohorts are limited [484]. Prospective data on cabozantinib and axitinib are available for patients progressing on immunotherapy, but these studies do not focus solely on the front-line setting, involve subset analyses, and are too small for definitive conclusions [472, 485].

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Retrospective data on VEGFR-TKI therapy after progression on front-line immune combinations exist but have significant limitations. When considering this data in totality, there is some activity but it is still too early to recommend one VEGFR-TKI over another after immunotherapy/immunotherapy or immunotherapy/VEGFR combination (Figure 7.2). After the axitinib plus pembrolizumab combination, changing the VEGFR-TKI at progression to cabozantinib or any other TKI not previously used is recommended. The Panel do not support the use of mTOR inhibitors unless VEGF-targeted therapy is contraindicated as they have been outperformed by other VEGF-targeted therapies in mRCC [486]. Drug choice in the third-line setting, after immune checkpoint inhibitor combinations and subsequent VEGF-targeted therapy, is unknown. The Panel recommends a subsequent agent which is approved in VEGF-refractory disease, with the exception of re-challenge with immune checkpoint blockade. Cabozantinib is the only agent in VEGF-refractory disease with RCT data showing a survival advantage and should be used preferentially [468]. Axitinib has positive PFS data in VEGF-refractory disease. Both sorafenib and everolimus have been outperformed by other agents in VEGFrefractory disease and are therefore less attractive [486]. The lenvatinib plus everolimus combination appears superior to everolimus alone and has been granted EMA regulatory approval based on randomised phase II data. This is an alternative despite the availability of phase II data only [476]. As shown in a study which also included patients on immune checkpoint inhibitors tivozinib provides PFS superiority over sorafenib in VEGFrefractory disease [487]. 7.4.6.2 Non-clear-cell metastatic RCC No phase III trials of patients with non-cc-mRCC have been reported. Expanded access programmes and subset analyses from RCC studies suggest the outcome of these patients with targeted therapy is poorer than for ccRCC. Targeted treatment in non-cc-mRCC has focused on temsirolimus, everolimus, sorafenib, sunitinib and pembrolizumab [438, 488-490]. The most common non-clear-cell subtypes are papillary type I and non-type I papillary RCCs. There are small single-arm trials for sunitinib and everolimus [490-493]. A trial of both types of pRCC treated with everolimus (RAPTOR), showed a median PFS of 3.7 months per central review in the ITT population with a median OS of 21.0 months [493]. In a non-randomised phase II trial, type 2 papillary RCC associated to HLRCC, a familial cancer syndrome caused by germline mutations in the fumarate hydratase enzyme (FH) gene, the combination of bevacizumab 10 mg/kg IV every 2 weeks and erlotinib 150 mg orally daily has been evaluated [494]. The combination regimen reports interesting activity with an ORR of 64% (27/42; 95% CI: 49–77) in the HLRCC cohort, with a median PFS of 21.1 months (95% CI: 15.6–26.6). Grade ≥ 3 treatmentrelated AEs occurred in 47% of patients, including hypertension (34%) and proteinuria (13%). However, a randomised phase II trial of everolimus vs. sunitinib (ESPN) with crossover design in non-cc-mRCC including 73 patients (27 with pRCC) was stopped after a futility analysis for PFS and OS [495]. The final results showed a non-significant trend favouring sunitinib (6.1 vs. 4.1 months). Based on a systematic review including subgroup analyses of the ESPN, RECORD-3 and another phase II trial (ASPEN), sunitinib and everolimus remain options in this population, with a preference for sunitinib [8, 144, 496]. Patients with non-cc-mRCC should be referred to a clinical trial, where appropriate. Efficacy for pembrolizumab (n = 165; response rates of 24%, PFS 4.1 months [95% CI: 2.8–5.6 months] 72% one-year OS) was noted but these results are based on a single-arm phase II study [447]. Pembrolizumab can be conceded in this setting due to the high unmet need. Subset analyses have shown impressive results for PD-L1 inhibitors combined with CTLA4 or VEGF-targeted therapy in renal tumours with sarcomatoid features. Bevacizumab/atezolizumab, ipilimumab/nivolumab, axitinib/pembrolizumab and avelumab/axitinib can all be recommended instead of VEFG-targeted therapy alone. These options have impressive OS advantages over sunitinib and superseded VEGF-targeted therapy. Collecting-duct cancers and renal medullary cancers are highly resistant to systemic therapy. Only case reports have been published for a spectrum of treatment options so far and no clear recommendations can be provided until data from international registries (RARECARE) or clinical trials become available.

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Figure 7.1: U  pdated EAU Guidelines recommendations for the first-line treatment of metastatic clear-cell RCC

Standard of Care

Alternative in patients who can not receive or tolerate immune checkpoint inhibitors

IMDC favourable risk

nivolumab/cabozantinib [1b] pembrolizumab/axitinib [1b] pembrolizumab/lenvatinib [1b]

sunitinib* [1b] pazopanib* [1b]

IMDC intermediate and poor risk

nivolumab/cabozantinib [1b] pembrolizumab/axitinib [1b] pembrolizumab/lenvatinib [1b] nivolumab/ipilimumab [1b]

cabozantinib* [2a] sunitinib*[1b] pazopanib* [1b]

IMDC = The International Metastatic Renal Cell Carcinoma Database Consortium *pazopanib for intermediate-risk disease only. [1b] = based on one randomised controlled phase III trial. [2a] = based on a well-designed study without randomisation, or a subgroup analysis of a randomised controlled trial. Figure 7.2: EAU Guidelines recommendations for later-line therapy

Standard of care

Prior IO

Any VEGF-targeted therapy that has not been used previously in combination with IO [4]

Prior TKI

nivolumab [1b] cabozantinib [1b]

Alternative

axitinib [2b]

IO = immunotherapy; TKI = tyrosine kinase inhibitors; VEGF = vascular endothelial growth factor. [1b] = based on one randomised controlled phase III trial. [2b] = subgroup analysis of a randomised controlled phase III trial. [4] = expert opinion. 7.4.7

Summary of evidence and recommendations for targeted therapy in metastatic RCC

Summary of evidence Single-agent VEGF-targeted therapy has been superseded by immune checkpoint-based combination therapy. Pazopanib is non-inferior to sunitinib in front-line mRCC. Cabozantinib in intermediate- and poor-risk treatment-naive clear-cell RCC leads to better response rates and PFS but not OS when compared to sunitinib. Tivozanib has been EMA approved, but the evidence is still considered inferior over existing choices in the front-line setting. Single-agent VEGF-targeted therapies are preferentially recommended after front-line PD-L1-based combinations. Re-challenge with treatments already used should be avoided.

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LE 1b 1b 2b 3 3

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Single-agent cabozantinib or nivolumab are superior to everolimus after one or more lines of VEGFtargeted therapy. Everolimus prolongs PFS after VEGF-targeted therapy when compared to placebo. This is no longer widely recommended before third-line therapy. Both mTOR inhibitors and VEGF-targeted therapies have limited activity in non-cc-mRCC. There is a non-significant trend for improved oncological outcomes for sunitinib over everolimus. Lenvatinib in combination with everolimus improved PFS over everolimus alone in VEGF-refractory disease. Its role after immune checkpoint inhibitors is uncertain. There is a lack of robust data on this combination making its recommendation challenging. Recommendations Offer nivolumab or cabozantinib for immune checkpoint inhibitor-naive vascular endothelial growth factor receptor (VEGFR)-refractory clear-cell metastatic renal cell carcinoma (cc-mRCC) after one or two lines of therapy. Sequencing the agent not used as second-line therapy (nivolumab or cabozantinib) for third-line therapy is recommended. Offer VEGF-tyrosine kinase inhibitors as second-line therapy to patients refractory to nivolumab plus ipilimumab or axitinib plus pembrolizumab or cabozantinib plus nivolumab or lenvatinib plus pembrolizumab. Offer cabozantinib after VEGF-targeted therapy in cc-mRCC. Sequence systemic therapy in treating mRCC.

7.5

1b 1b 2a 2a

Strength rating Strong

Weak Weak

Strong Strong

Locally recurrent RCC after treatment of localised disease

Locally recurrent disease can either affect the tumour-bearing kidney after PN or focal ablative therapy such as RFA and cryotherapy. Local relapse may be due to the incomplete resection of the primary tumour (type A), in a minority of the cases to the local spread of the tumour by microvascular embolisation (type B), or true multifocality (type C) [497]. Most studies reporting on the oncological efficacy of surgery for recurrent disease after removal of the kidney have not considered the traditional definition of local recurrence after RN, PN and thermal ablation, which is: “tumour growth exclusively confined to the true renal fossa”. Instead, recurrences within the renal vein, the ipsilateral adrenal gland or the regional LNs were included under this term. Isolated tumour recurrence within the true renal fossa only is a rare event. In the existing literature the topic is poorly investigated and available data are mainly related to positive surgical margins only [498, 499]. The prognosis of recurrent disease not due to multifocality (type A and B) is poor, despite salvage nephrectomy [497]. Recurrent tumour growth in the regional LNs or ipsilateral adrenal gland may reflect metachronous metastatic spread (see Section 7.3). After PN for pT1 disease, recurrences within the remaining kidney occur in 0.5–2% of patients [500, 501]. Following thermal ablation or cryotherapy generally intra-renal, but also peri-renal, recurrences have been reported in up to 14% of cases [502]. Whereas repeat ablation is still recommended as the preferred therapeutic option after treatment failure, the most effective salvage procedure as an alternative to complete nephrectomy has not yet been defined. Isolated local recurrence is associated with worse survival [503, 504]. Based on retrospective and non-comparative data only, several approaches such as surgical excision, radiotherapy, systemic treatment and observation have been suggested for the treatment of isolated local recurrence [505-507]. Among these alternatives, surgical resection with negative margins remains the only therapeutic option shown to be associated with improved survival [503] One of the largest series including 2,945 patients treated with RN reported on 54 patients with recurrent disease localised in the renal fossa, the ipsilateral adrenal gland or the regional LNs as sole metastatic sites [505]. Another recent series identified 33 patients with isolated local recurrences and 30 local recurrences with synchronous metastases within a cohort of 2,502 surgically treated patients, confirming the efficacy of locally directed treatment vs. conservative approaches (observation, systemic therapy) [508]. In a series of 1,955 patients with clinical T1 RCCs treated with PN, 95 patients (4.9%) had a pT3a upstaging, indicating a high risk for local and intra-renal recurrence and reduced survival [506]. Open surgery has been successfully reported in studies [509, 510]. However, minimaly invasive approaches, including standard and hand-assisted laparoscopic- and robotic approaches for the resection of isolated RCC recurrences have been occasionally reported. Ablative therapies including cryoablation, radiofrequency and microwave ablation, may also have a role in managing recurrent RCC patients, but further validation will be needed [511].

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In summary, the limited available evidence suggests that in selected patients surgical removal of locally recurrent disease can induce durable tumour control, although with expected high risk of complications. Johnson et al. published on 51 planned repeat PNs in 47 patients with locally recurrent disease, reporting a total of 40 peri-operative complications, with temporary urinary extravasation being the most prevalent [512]. Since local recurrences develop early, with a median time interval of 10–20 months after treatment of the primary tumour [513], a guideline-adapted follow-up scheme for early detection is recommended (see Chapter 8 - Follow-up) even though benefit in terms of cancer control has not yet been demonstrated [514]. Adverse prognostic parameters are a short time interval since treatment of the primary tumour (< 3–12 months) [515], sarcomatoid differentiation of the recurrent lesion and incomplete surgical resection [505]. In case complete surgical removal is unlikely to be performed or when significant comorbidities are present (especially when combined with poor prognostic tumour features), palliative therapeutic approaches including radiation therapy aimed at symptom control and prevention of local complications should be considered (see Sections 7.3 and 7.4). 7.5.1

Summary of evidence and recommendation on locally recurrent RCC after treatment of localised disease

Summary of evidence Isolated recurrence is a rare entity (< 2%). In the absence of adverse prognostic factors such as sarcomatoid features or median time interval of < 12 months since treatment of the primary tumour, treatment of local recurrences can induce durable local control. The most optimal modality of local treatment for locally recurrent RCC is still under debate.

Recommendation Offer local treatment of locally recurrent disease when technically possible and significant comorbidities are absent.

8.

FOLLOW-UP IN RCC

8.1

Introduction

LE 3 3

3

Strength rating Weak

Surveillance after treatment for RCC allows the urologist to monitor or identify: • post-operative complications; • renal function; • local recurrence; • recurrence in the contralateral kidney; • distant metastases; • cardiovascular events. There is no consensus on follow-up strategies after RCC treatment, with limited evidence suggesting that more frequent post-operative imaging intervals do not provide any improvement for early detection of recurrence that would lead to improved survival [514]. As such, intensive radiological surveillance may not be necessary for all patients. Follow-up is also important to assess functional outcomes and to limit long-term sequelae such as renal function impairment, end-stage renal disease and cardiovascular events [516]. Currently, the key question is whether any recurrence detection during follow-up and subsequent treatment will lead to any meaningful change in survival outcome for these patients. In contrast to high-grade and/or locally advanced disease, the outcome after surgery for T1a low-grade tumours is almost always excellent. It is therefore reasonable to stratify follow-up, taking into account the risk of each different RCC to develop a local or distant recurrence. Although there is no randomised evidence, large studies have examined prognostic factors with long follow-up [168, 517, 518] (LE: 4). One study has shown a survival benefit in patients who were followed within a structured surveillance protocol vs. patients who were not [519]; patients undergoing follow-up seem to have a longer OS when compared to patients not undergoing routine follow-up [519].

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Furthermore, an individualised and risk-based approach to RCC follow-up has recently been proposed. The authors used competing risk models, incorporating patient age, pathologic stage, relapse location and comorbidities, to calculate when the risk of non-RCC death exceeds the risk of RCC recurrence [520]. For patients with low-stage disease but with a Charlson comorbidity index ≥ 2, the risk of non-RCC death exceeded that of abdominal recurrence risk already one month after surgery, regardless of patient age. The RECUR consortium, initiated by this Panel, collects similar data with the aim to provide comparators for guideline recommendations. Recently published RECUR data support a risk-based approach; more specifically a competing-risk analysis showed that for low-risk patients, the risk of non-RCC related death exceeded the risk of RCC recurrence shortly after the intial surgery. For intermediate-risk patients, the corresponding time point was reached around four to five years after surgery. In high-risk patients, the risk of RCC recurrence continously exceeded the risk of non-RCC related death [10]. In the near future, genetic profiling may refine the existing prognostic scores and external validation in datasets from adjuvant trials have been promising in improving stratification of patient’s risk of recurrence [10, 521]. Recurrence after PN is rare, but early diagnosis is relevant, as the most effective treatment is surgery [509, 522]. Recurrence in the contralateral kidney is rare (1–2%) and can occur late (median 5–6 years) [523] (LE: 3). Follow-up can identify local recurrences or metastases at an early stage. In metastatic disease, extended tumour growth can limit the opportunity for surgical resection, which is considered the standard therapy in cases of resectable and preferably solitary lesions. In addition, early diagnosis of tumour recurrence may enhance the efficacy of systemic treatment if the tumour burden is low.

8.2 •

• • •

Which imaging investigations for which patients, and when? The sensitivity of chest radiography and US for detection of small RCC metastases is poor. The sensitivity of chest radiography is significantly lower than CT-scans, as proven in comparative studies including histological evaluation [524-526]. Therefore, follow-up for recurrence detection with chest radiography and US are less sensitive [527]. Positron-emission tomography and PET-CT as well as bone scintigraphy should not be used routinely in RCC follow-up, due to their limited specificity and sensitivity [6, 119]. Surveillance should also include evaluation of renal function and cardiovascular risk factors [516]. Outside the scope of regular follow-up imaging of the chest and abdomen, targeted imaging should be considered in patients with organ-specific symptoms, e.g. CT or MRI imaging of the brain in patients experiencing neurological symptoms [528].

Controversy exists on the optimal duration of follow-up. Some authors argue that follow-up with imaging is not cost-effective after five years; however, late metastases are more likely to be solitary and justify more aggressive therapy with curative intent. In addition, patients with tumours that develop in the contralateral kidney can be treated with NSS if the tumours are detected early. Several authors have designed scoring systems and nomograms to quantify the likelihood of patients to develop tumour recurrences, metastases, and subsequent death [215, 217, 529, 530]. These models, of which the most utilised are summarised in Chapter 6 - Prognosis, have been compared and validated [531] (LE: 2). Using prognostic variables, several stage-based follow-up regimens have been proposed, although, none propose follow-up strategies after ablative therapies [532, 533]. A post-operative nomogram is available to estimate the likelihood of freedom from recurrence at five years [212]. Recently, a pre-operative prognostic model based on age, symptoms and TNM staging has been published and validated [534] (LE: 3). A follow-up algorithm for monitoring patients after treatment for RCC is needed, recognising not only the patient’s risk of recurrence profile, but also the efficacy of the treatment given (Table 8.1). These prognostic systems can be used to adapt the follow-up schedule according to predicted risk of recurrence. Ancillary to the above, life-expectancy calculations based on comorbidity and age at diagnosis may be useful in counselling patients on duration of follow-up [535].

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Table 8.1: Proposed follow-up schedule following treatment for localised RCC, taking into account patient risk of recurrence profile and treatment efficacy (based on expert opinion [LE: 4]) Risk profile (*)

Oncological follow-up after date of surgery 3 mo 6 mo 12 mo 18 mo 24 mo 30 mo 36 mo > 3 yr (**) (***) > 5 yr (**) (***) Low risk of recurrence CT CT CT CT once every two yrs For ccRCC: Leibovich Score 0-2 For non-ccRCC: pT1a-T1b pNx-0 M0 and histological grade 1 or 2. Intermediate risk of recurrence

CT

CT

-

CT

-

CT

CT once yr

CT once every two yrs

CT

CT

CT

CT

-

CT

CT once yr

CT once every two yrs

For ccRCC: Leibovich Score 3-5 For non-ccRCC: pT1b pNx-0 and/or histological grade 3 or 4. High risk of recurrence CT For ccRCC: Leibovich Score ≥ 6 For non-ccRCC: pT2-pT4 with any histological grade or pT any, pN1 cM0 with any histological grade ccRCC = clear cell renal cell carcinoma, CT = computed tomography, mo = months, non-ccRCC = non clear cell renal cell carcinoma; yr = years. The table above provides recommendations on follow-up strategies for low, intermediate and high risk of recurrence in patients curatively treated for localised RCC either with NSS or RN. Computed tomography in the table refers to imaging of both chest and abdomen. Alternatively, MRI of the abdomen can be performed instead of a CT-scan. * R  isk of recurrence profiles should be based on validated prognostic models. The EAU RCC Guidelines Panel recommends the 2003 Leibovich model for ccRCC [215]. However, other validated models can be used by physicians based on their own national/regional recommendations. In a similar fashion, for curatively treated localised non-ccRCC, the Panel recommends the use of the University of California Los Angeles integrated staging system (UISS) to determine risk of recurrence [216]. ** for all risk of recurrence profiles, functional follow-up, mainly monitoring renal and cardiovascular function, may continue according to specific clinical needs irrespective of the length of the oncological follow-up. *** F  or low-risk profiles at > 3 years and intermediate-risk at > 5 years of follow-up respectively, consider counselling patients about terminating oncological follow-up imaging based on assessment of comorbidities, age, life expectancy and/or patient wishes.

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8.3

Summary of evidence and recommendations for surveillance following RN or PN or ablative therapies in RCC

Summary of evidence Functional follow-up after curative treatment for RCC is useful to prevent renal and cardiovascular deterioration. Oncological follow-up can detect local recurrence or metastatic disease while the patient may still be surgically curable. After NSS, there is an increased risk of recurrence for larger (> 7 cm) tumours, or when there is a positive surgical margin. Patients undergoing follow-up have a better overall survival than patients not undergoing surveillance. Prognostic models provide stratification of RCC risk of recurrence based on TNM and histological features. In competing-risk models, risk of non-RCC-related death exceeds that of RCC recurrence or related death in low-risk patients. Life expectancy estimation is feasible and may support counselling of patients on duration of follow-up. Recommendations Base follow-up after treatment of localised RCC on the risk of recurrence. Perform functional follow-up (renal function assessment and prevention of cardiovascular events) both in nephron-sparing (NSS) and radical nephrectomy patients. Intensify follow-up in patients after nephron-sparing surgery for tumours > 7 cm or in patients with a positive surgical margin. Consider curtailing follow-up when the risk of dying from other causes is double that of recurrence risk. Base risk of recurrence stratification on validated subtype-specific models such as the Leibovich Score for ccRCC or the University of California Los Angeles integrated staging system (UISS) for non-ccRCC.

8.4

LE 4 4 3 3 3 3 4

Strength rating Strong Weak Weak Weak Weak

Research priorities

There is a clear need for future research to determine whether follow-up can optimise patient survival. Data evaluating at which time point follow-up has the highest chance to detect recurrence will be most valuable for clinical practice. Novel prognostic markers at surgery should be investigated to determine the risk of relapse over time.

9.

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1.

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Patel, P.H., et al. Targeting von Hippel-Lindau pathway in renal cell carcinoma. Clin Cancer Res, 2006. 12: 7215. https://pubmed.ncbi.nlm.nih.gov/17189392 Yang, J.C., et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med, 2003. 349: 427. https://pubmed.ncbi.nlm.nih.gov/12890841 Patard, J.J., et al. Understanding the importance of smart drugs in renal cell carcinoma. Eur Urol, 2006. 49: 633. https://pubmed.ncbi.nlm.nih.gov/16481093 Escudier, B., et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med, 2007. 356: 125. https://pubmed.ncbi.nlm.nih.gov/17215530 Bellmunt, J., et al. The medical treatment of metastatic renal cell cancer in the elderly: position paper of a SIOG Taskforce. Crit Rev Oncol Hematol, 2009. 69: 64. https://pubmed.ncbi.nlm.nih.gov/18774306 Motzer, R.J., et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol, 2009. 27: 3584. https://pubmed.ncbi.nlm.nih.gov/19487381 Motzer, R.J., et al. Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as first-line therapy for advanced renal cell carcinoma. J Clin Oncol, 2012. 30: 1371. https://pubmed.ncbi.nlm.nih.gov/22430274 Bracarda, S., et al. Sunitinib administered on 2/1 schedule in patients with metastatic renal cell carcinoma: the RAINBOW analysis. Ann Oncol, 2016. 27: 366. https://pubmed.ncbi.nlm.nih.gov/26685011 Jonasch, E., et al. A randomized phase 2 study of MK-2206 versus everolimus in refractory renal cell carcinoma. Ann Oncol, 2017. 28: 804. https://pubmed.ncbi.nlm.nih.gov/28049139 Sternberg, C.N., et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol, 2010. 28: 1061. https://pubmed.ncbi.nlm.nih.gov/20100962 Motzer, R.J., et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med, 2013. 369: 722. https://pubmed.ncbi.nlm.nih.gov/23964934 Escudier, B., et al. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study. J Clin Oncol, 2014. 32: 1412. https://pubmed.ncbi.nlm.nih.gov/24687826 Rini, B.I., et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet, 2011. 378: 1931. https://pubmed.ncbi.nlm.nih.gov/22056247 Dror Michaelson M., et al. Phase III AXIS trial of axitinib versus sorafenib in metastatic renal cell carcinoma: Updated results among cytokine-treated patients. J Clin Oncol 2012. J Clin Oncol 30: 15 suppl; abstr 4546. https://ascopubs.org/doi/abs/10.1200/jco.2012.30.15_suppl.4546 Motzer, R.J., et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol, 2013. 14: 552. https://pubmed.ncbi.nlm.nih.gov/23598172 Hutson, T.E., et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol, 2013. 14: 1287. https://pubmed.ncbi.nlm.nih.gov/24206640 Choueiri, T.K., et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med, 2015. 373: 1814. https://pubmed.ncbi.nlm.nih.gov/26406150 Choueiri, T.K., et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol, 2016. 17: 917. https://pubmed.ncbi.nlm.nih.gov/27279544 Choueiri, T.K., et al. Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. J Clin Oncol, 2017. 35: 591. https://pubmed.ncbi.nlm.nih.gov/28199818

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Choueiri, T.K., et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): Progressionfree survival by independent review and overall survival update. Eur J Cancer, 2018. 94: 115. https://pubmed.ncbi.nlm.nih.gov/29550566 Motzer, R.J., et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol, 2015. 16: 1473. https://pubmed.ncbi.nlm.nih.gov/26482279 Motzer, R.J., et al. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol, 2013. 31: 3791. https://pubmed.ncbi.nlm.nih.gov/24019545 Molina, A.M., et al. Efficacy of tivozanib treatment after sorafenib in patients with advanced renal cell carcinoma: crossover of a phase 3 study. Eur J Cancer, 2018. 94: 87. https://pubmed.ncbi.nlm.nih.gov/29547835 Escudier B., et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol, 2010. 28: 2144. https://pubmed.ncbi.nlm.nih.gov/16860997 Rini, B.I., et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol, 2008. 26: 5422. https://pubmed.ncbi.nlm.nih.gov/18936475 Rini, B.I., et al. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol, 2010. 28: 2137. https://pubmed.ncbi.nlm.nih.gov/20368558 Larkin, J.M., et al. Kinase inhibitors in the treatment of renal cell carcinoma. Crit Rev Oncol Hematol, 2006. 60: 216. https://www.sciencedirect.com/science/article/pii/S104084280600117X Motzer, R.J., et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet, 2008. 372: 449. https://pubmed.ncbi.nlm.nih.gov/18653228 Auvray, M., et al. Second-line targeted therapies after nivolumab-ipilimumab failure in metastatic renal cell carcinoma. Eur J Cancer, 2019. 108: 33. https://pubmed.ncbi.nlm.nih.gov/30616146 Ornstein, M.C., et al. Prospective phase II multi-center study of individualized axitinib (Axi) titration for metastatic renal cell carcinoma (mRCC) after treatment with PD-1 / PD-L1 inhibitors. J Clin Oncol, 2018. 36. https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.4517 Coppin, C., et al. Targeted therapy for advanced renal cell cancer (RCC): a Cochrane systematic review of published randomised trials. BJU Int, 2011. 108: 1556. https://pubmed.ncbi.nlm.nih.gov/21952069 Rini, B.I., et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol, 2020. 21: 95. https://pubmed.ncbi.nlm.nih.gov/31810797 Gore, M.E., et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expandedaccess trial. Lancet Oncol, 2009. 10: 757. https://pubmed.ncbi.nlm.nih.gov/19615940 Sánchez P., et al. Non-clear cell advanced kidney cancer: is there a gold standard? Anticancer Drugs 2011. 22 S9. https://pubmed.ncbi.nlm.nih.gov/21173605 Koh, Y., et al. Phase II trial of everolimus for the treatment of nonclear-cell renal cell carcinoma. Ann Oncol, 2013. 24: 1026. https://pubmed.ncbi.nlm.nih.gov/23180114 Tannir, N.M., et al. A phase 2 trial of sunitinib in patients with advanced non-clear cell renal cell carcinoma. Eur Urol, 2012. 62: 1013. https://pubmed.ncbi.nlm.nih.gov/22771265 Ravaud A, et al. First-line sunitinib in type I and II papillary renal cell carcinoma (PRCC): SUPAP, a phase II study of the French Genito-Urinary Group (GETUG) and the Group of Early Phase trials (GEP) J. Clin Oncol, 2009. Vol 27, No 15S: 5146. https://ascopubs.org/doi/abs/10.1200/jco.2009.27.15_suppl.5146

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Escudier, B., et al. Open-label phase 2 trial of first-line everolimus monotherapy in patients with papillary metastatic renal cell carcinoma: RAPTOR final analysis. Eur J Cancer, 2016. 69: 226. https://pubmed.ncbi.nlm.nih.gov/27680407 Srinivasan, R., et al. Results from a phase II study of bevacizumab and erlotinib in subjects with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) or sporadic papillary renal cell cancer. J Clin Oncol, 2020. 38: 15 Suppl. 5004. https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.5004 Tannir, N.M., et al. Everolimus Versus Sunitinib Prospective Evaluation in Metastatic Non-Clear Cell Renal Cell Carcinoma (ESPN): A Randomized Multicenter Phase 2 Trial. Eur Urol, 2016. 69: 866. https://pubmed.ncbi.nlm.nih.gov/26626617 Armstrong, A.J., et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol, 2016. 17: 378. https://ascopubs.org/doi/abs/10.1200/jco.2015.33.15_suppl.4507 Antonelli, A., et al. Features of Ipsilateral Renal Recurrences After Partial Nephrectomy: A Proposal of a Pathogenetic Classification. Clin Genitourin Cancer, 2017. 15: 540. https://pubmed.ncbi.nlm.nih.gov/28533051 Petros, F.G., et al. Oncologic outcomes of patients with positive surgical margin after partial nephrectomy: a 25-year single institution experience. World J Urol, 2018. 36: 1093. https://pubmed.ncbi.nlm.nih.gov/29488096 Bansal, R.K., et al. Positive surgical margins during partial nephrectomy for renal cell carcinoma: Results from Canadian Kidney Cancer information system (CKCis) collaborative. Can Urol Assoc J, 2017. 11: 182. https://pubmed.ncbi.nlm.nih.gov/28652876 Bertolo, R., et al. Low Rate of Cancer Events After Partial Nephrectomy for Renal Cell Carcinoma: Clinicopathologic Analysis of 1994 Cases with Emphasis on Definition of “Recurrence”. Clin Genitourin Cancer, 2019. 17: 209. https://pubmed.ncbi.nlm.nih.gov/31000486 Kreshover, J.E., et al. Renal cell recurrence for T1 tumors after laparoscopic partial nephrectomy. J Endourol, 2013. 27: 1468. https://pubmed.ncbi.nlm.nih.gov/24074156 Wah, T.M., et al. Radiofrequency ablation (RFA) of renal cell carcinoma (RCC): experience in 200 tumours. BJU Int, 2014. 113: 416. https://pubmed.ncbi.nlm.nih.gov/24053769 Itano, N.B., et al. Outcome of isolated renal cell carcinoma fossa recurrence after nephrectomy. J Urol, 2000. 164: 322. https://pubmed.ncbi.nlm.nih.gov/10893575 Lee, Z., et al. Local Recurrence Following Resection of Intermediate-High Risk Nonmetastatic Renal Cell Carcinoma: An Anatomical Classification and Analysis of the ASSURE (ECOG-ACRIN E2805) Adjuvant Trial. J Urol, 2020. 203: 684. https://pubmed.ncbi.nlm.nih.gov/31596672 Margulis, V., et al. Predictors of oncological outcome after resection of locally recurrent renal cell carcinoma. J Urol, 2009. 181: 2044. https://pubmed.ncbi.nlm.nih.gov/19286220 Russell, C.M., et al. Multi-institutional Survival Analysis of Incidental Pathologic T3a Upstaging in Clinical T1 Renal Cell Carcinoma Following Partial Nephrectomy. Urology, 2018. 117: 95. https://pubmed.ncbi.nlm.nih.gov/29678662 Srivastava, A., et al. Incidence of T3a up-staging and survival after partial nephrectomy: Sizestratified rates and implications for prognosis. Urol Oncol, 2018. 36: 12.e7. https://pubmed.ncbi.nlm.nih.gov/28970053 Psutka, S.P., et al. Renal fossa recurrence after nephrectomy for renal cell carcinoma: prognostic features and oncological outcomes. BJU Int, 2017. 119: 116. https://pubmed.ncbi.nlm.nih.gov/27489013 Sandhu, S.S., et al. Surgical excision of isolated renal-bed recurrence after radical nephrectomy for renal cell carcinoma. BJU Int, 2005. 95: 522. https://pubmed.ncbi.nlm.nih.gov/15705072 Master, V.A., et al. Management of isolated renal fossa recurrence following radical nephrectomy. J Urol, 2005. 174: 473. https://pubmed.ncbi.nlm.nih.gov/16006867

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Ierardi, A.M., et al. Percutaneous microwave ablation therapy of renal cancer local relapse after radical nephrectomy: a feasibility and efficacy study. Med Oncol, 2020. 37: 27. https://pubmed.ncbi.nlm.nih.gov/32166412 Johnson, A., et al. Feasibility and outcomes of repeat partial nephrectomy. J Urol, 2008. 180: 89. https://pubmed.ncbi.nlm.nih.gov/18485404 Mouracade, P., et al. Imaging strategy and outcome following partial nephrectomy. Urol Oncol, 2017. 35: 660.e1. https://pubmed.ncbi.nlm.nih.gov/28863862 Dabestani, S., et al. Increased use of cross-sectional imaging for follow-up does not improve postrecurrence survival of surgically treated initially localized R.C.C.: results from a European multicenter database (R.E.C.U.R.). Scand J Urol, 2019. 53: 14. https://pubmed.ncbi.nlm.nih.gov/30907214 Rieken, M., et al. Predictors of Cancer-specific Survival After Disease Recurrence in Patients With Renal Cell Carcinoma: The Effect of Time to Recurrence. Clin Genitourin Cancer, 2018. 16: e903. https://pubmed.ncbi.nlm.nih.gov/29653814 Capitanio, U., et al. Hypertension and Cardiovascular Morbidity Following Surgery for Kidney Cancer. Eur Urol Oncol, 2020. 3: 209. https://pubmed.ncbi.nlm.nih.gov/31411993 Lam, J.S., et al. Renal cell carcinoma 2005: new frontiers in staging, prognostication and targeted molecular therapy. J Urol, 2005. 173: 1853. https://pubmed.ncbi.nlm.nih.gov/15879764 Scoll, B.J., et al. Age, tumor size and relative survival of patients with localized renal cell carcinoma: a surveillance, epidemiology and end results analysis. J Urol, 2009. 181: 506. https://pubmed.ncbi.nlm.nih.gov/19084868 Beisland, C., et al. A prospective risk-stratified follow-up programme for radically treated renal cell carcinoma patients: evaluation after eight years of clinical use. World J Urol, 2016. 34: 1087. https://pubmed.ncbi.nlm.nih.gov/26922650 Stewart-Merrill, S.B., et al. Oncologic Surveillance After Surgical Resection for Renal Cell Carcinoma: A Novel Risk-Based Approach. J Clin Oncol, 2015. 33: 4151. https://pubmed.ncbi.nlm.nih.gov/26351352 Rini, B.I., et al. Validation of the 16-Gene Recurrence Score in Patients with Locoregional, High-Risk Renal Cell Carcinoma from a Phase III Trial of Adjuvant Sunitinib. Clin Cancer Res, 2018. 24: 4407. https://pubmed.ncbi.nlm.nih.gov/29773662 Bruno, J.J., 2nd, et al. Renal cell carcinoma local recurrences: impact of surgical treatment and concomitant metastasis on survival. BJU Int, 2006. 97: 933. https://pubmed.ncbi.nlm.nih.gov/16643473 Bani-Hani, A.H., et al. Associations with contralateral recurrence following nephrectomy for renal cell carcinoma using a cohort of 2,352 patients. J Urol, 2005. 173: 391. https://pubmed.ncbi.nlm.nih.gov/15643178 Schaner, E.G., et al. Comparison of computed and conventional whole lung tomography in detecting pulmonary nodules: a prospective radiologic-pathologic study. Am J Roentgenol, 1978. 131: 51. https://pubmed.ncbi.nlm.nih.gov/97985 Patel, T. Lung Metastases Imaging. 2017. https://emedicine.medscape.com/article/358090-overview Chang, A.E., et al. Evaluation of computed tomography in the detection of pulmonary metastases: a prospective study. Cancer, 1979. 43: 913. https://pubmed.ncbi.nlm.nih.gov/284842 Doornweerd, B.H., et al. Chest X-ray in the follow-up of renal cell carcinoma. World J Urol, 2014. 32: 1015. https://pubmed.ncbi.nlm.nih.gov/24096433 Sountoulides, P., et al. Atypical presentations and rare metastatic sites of renal cell carcinoma: a review of case reports. J Med Case Rep, 2011. 5: 429. https://pubmed.ncbi.nlm.nih.gov/21888643 Kattan, M.W., et al. A postoperative prognostic nomogram for renal cell carcinoma. J Urol, 2001. 166: 63. https://pubmed.ncbi.nlm.nih.gov/11435824 Lam, J.S., et al. Postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma based on a validated prognostic nomogram and risk group stratification system. J Urol, 2005. 174: 466. https://pubmed.ncbi.nlm.nih.gov/16006866

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10. CONFLICT OF INTEREST All members of the Renal Cell Cancer Guidelines Panel have provided disclosure statements of all relationships that they have that might be perceived as a potential source of a conflict of interest. This information is publically accessible through the European Association of Urology website: https://uroweb.org/guideline/ renalcell-carcinoma/?type=panel/. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

11. CITATION INFORMATION The format in which to cite the EAU Guidelines will vary depending on the style guide of the journal in which the citation appears. Accordingly, the number of authors or whether, for instance, to include the publisher, location, or an ISBN number may vary. The compilation of the complete Guidelines should be referenced as: EAU Guidelines. Edn. presented at the EAU Annual Congress Milan 2021. ISBN 978-94-92671-13-4. If a publisher and/or location is required, include: EAU Guidelines Office, Arnhem, The Netherlands. http://uroweb.org/guidelines/compilations-of-all-guidelines/ References to individual guidelines should be structured in the following way: Contributors’ names. Title of resource. Publication type. ISBN. Publisher and publisher location, year.

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EAU Guidelines on Sexual and Reproductive Health A. Salonia (Chair), C. Bettocchi, J. Carvalho, G. Corona, T.H. Jones, A. Kadioglu, ˇ J.I. Martinez-Salamanca, S. Minhas (Vice-chair), E.C. Serefoglu, ˇ P. Verze Guidelines Associates: L. Boeri, P. Capogrosso, A. Cocci, K. Dimitropoulos, M. Gül, G. Hatzichristodoulou, A. Kalkanli, V. Modgil, U. Milenkovic, G. Russo, T. Tharakan

© European Association of Urology 2021

TABLE OF CONTENTS

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1. INTRODUCTION 1.1 Aims and Objectives 1.2 Panel composition 1.3 Available Publications 1.4 Publication History 1.5 Changes in the Guideline for 2021

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2. METHODOLOGY 2.1 Methods 2.2 Review 2.3 Future goals

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3. MALE HYPOGONADISM 3.1 Epidemiology and prevalence of male hypogonadism 3.1.1 Body Composition and Metabolic Profile 3.1.2 Metabolic Syndrome/Type 2 Diabetes 3.2 Physiology of testosterone production 3.2.1 Circulation and transport of testosterone 3.2.2 Androgen receptor 3.3 Role of testosterone in male sexual and reproductive health 3.3.1 Sexual development and maturation 3.3.2 Sexual function 3.4 Classification and causes of male hypogonadism 3.5 Late-onset hypogonadism 3.5.1 Diagnostic evaluation 3.5.2 History taking 3.5.3 Physical examination 3.5.4 Summary of evidence and recommendations for the diagnostic evaluation of LOH 3.5.5 Recommendations for screening men with LOH 3.6 Treatment of LOH 3.6.1 Indications and contraindications for treatment of LOH 3.6.2 Testosterone therapy outcomes 3.6.2.1 Sexual dysfunction 3.6.2.2 Body composition and metabolic profile 3.6.2.3 Mood and cognition 3.6.2.4 Bone 3.6.2.5 Vitality and physical strength 3.6.2.6 Summary of evidence and recommendations for testosterone therapy outcome 3.6.3 Choice of treatment 3.6.3.1 Lifestyle factors 3.6.3.2 Medical preparations 3.6.3.2.1 Oral formulations 3.6.3.2.2 Parenteral formulations 3.6.3.2.3 Transdermal testosterone preparations 3.6.3.2.4 Transmucosal formulations 3.6.3.2.4.1 Transbuccal Testosterone preparations 3.6.3.2.4.2 Transnasal testosterone preparations 3.6.3.2.5 Subdermal depots 3.6.3.2.6 Anti-oestrogens 3.6.3.2.7 Gonadotropins 3.6.3.3 Summary of evidence and recommendations for choice of treatment for LOH 3.7 Safety and follow-up in hypogonadism management 3.7.1 Hypogonadism and fertility issues 3.7.2 Male breast cancer 3.7.3 Lower urinary tract symptoms/benign prostatic hyperplasia

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3.7.4 Prostate cancer (PCa) 3.7.5 Cardiovascular Disease 3.7.5.1 Cardiac Failure 3.7.6 Erythrocytosis 3.7.7 Obstructive Sleep Apnoea 3.7.8 Follow up 3.7.9 Summary of evidence and recommendations on risk factors in testosterone treatment

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4. EPIDEMIOLOGY AND PREVALENCE OF SEXUAL DYSFUNCTION AND DISORDERS OF MALE REPRODUCTIVE HEALTH 4.1 Erectile dysfunction 4.2 Premature ejaculation 4.3 Other ejaculatory disorders 4.3.1 Delayed ejaculation 4.3.2 Anejaculation and Anorgasmia 4.3.3 Retrograde ejaculation 4.3.4 Painful ejaculation 4.3.5 Haemospermia 4.4 Low sexual desire

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5. MANAGEMENT OF ERECTILE DYSFUNCTION 5.1 Definition and classification 5.2 Risk factors 5.3 Pathophysiology 5.3.1 Pelvic surgery and prostate cancer treatment 5.3.2 Summary of evidence on the epidemiology/aetiology/pathophysiology of ED 5.4 Diagnostic evaluation (basic work-up) 5.4.1 Medical and sexual history 5.4.2 Physical examination 5.4.3 Laboratory testing 5.4.4 Cardiovascular system and sexual activity: the patient at risk 5.4.4.1 Low-risk category 5.4.4.2 Intermediate- or indeterminate-risk category 5.4.4.3 High-risk category 5.5 Diagnostic Evaluation (advanced work-up) 5.5.1 Nocturnal penile tumescence and rigidity test 5.5.2 Intracavernous injection test 5.5.3 Dynamic duplex ultrasound of the penis 5.5.4 Arteriography and dynamic infusion cavernosometry or cavernosography 5.5.5 Psychiatric and psychosocial assessment 5.5.6 Recommendations for diagnostic evaluation of ED 5.6 Treatment of erectile dysfunction 5.6.1 Patient education - consultation and referrals 5.6.2 Treatment options 5.6.2.1 Oral pharmacotherapy 5.6.2.2 Topical/Intraurethral alprostadil 5.6.2.3 Shockwave therapy 5.6.2.4 Psychosexual counselling and therapy 5.6.2.5 Hormonal treatment 5.6.2.6 Vacuum erection devises 5.6.2.7 Intracavernous injections therapy 5.6.2.7.1 Alprostadil 5.6.2.8 Combination therapy 5.6.2.8.1 Erectile dysfunction after radical prostatectomy 5.6.2.9 Vascular surgery 5.6.2.9.1 Surgery for post-traumatic arteriogenic ED 5.6.2.9.2 Venous ligation surgery 5.6.2.9.3 Penile prostheses 5.6.2.9.4 Penile prostheses implantation: complications

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5.6.2.9.4.1 Conclusions about penile prostheses implantation 5.6.3 Recommendations for treatment of ED 5.6.4 Follow-up 6. DISORDERS OF EJACULATION 6.1 Introduction 6.2 Premature ejaculation 6.2.1 Epidemiology 6.2.2 Pathophysiology and risk factors 6.2.3 Impact of PE on quality of life 6.2.4 Classification 6.2.5 Diagnostic evaluation 6.2.5.1 Intravaginal ejaculatory latency time (IELT) 6.2.5.2 Premature ejaculation assessment questionnaires 6.2.5.3 Physical examination and investigations 6.2.5.4 Recommendations for the diagnostic evaluation of PE 6.2.6 Disease management 6.2.6.1 Psychological aspects and intervention 6.2.6.1.1 Recommendation for the assessment and treatment (psychosexual approach) of PE 6.2.6.2 Pharmacotherapy 6.2.6.2.1 Dapoxetine 6.2.6.2.2 Off-label use of antidepressants: selective serotonin reuptake inhibitors and clomipramine 6.2.6.2.3 Topical anaesthetic agents 6.2.6.2.3.1 Lidocaine/prilocaine cream 6.2.6.2.3.2 Lidocaine/prilocaine spray 6.2.6.2.4 Tramadol 6.2.6.2.5 Phosphodiesterase type 5 inhibitors 6.2.6.2.6 Other drugs 6.2.7 Summary of evidence on the epidemiology/aetiology/pathophysiology of PE 6.2.8 Recommendations for the treatment of PE 6.3 Delayed Ejaculation 6.3.1 Definition and classification 6.3.2 Pathophysiology and risk factors 6.3.3 Investigation and treatment 6.3.3.1 Psychological aspects and intervention 6.3.3.2 Pharmacotherapy 6.4 Anejaculation 6.4.1 Definition and classification 6.4.2 Pathophysiology and risk factors 6.4.3 Investigation and treatment 6.5 Painful Ejaculation 6.5.1 Definition and classification 6.5.2 Pathophysiology and risk factors 6.5.3 Investigation and treatment 6.5.3.1 Surgical intervention 6.6 Retrograde ejaculation 6.6.1 Definition and classification 6.6.2 Pathophysiology and risk factors 6.6.3 Disease management 6.6.3.1 Pharmacological 6.6.3.2 Management of infertility 6.7 Anorgasmia 6.7.1 Definition and classification 6.7.2 Pathophysiology and risk factors 6.7.3 Disease management 6.7.3.1 Psychological/behavioural strategies 6.7.3.2 Pharmacotherapy

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6.7.3.3 Management of infertility 6.8 Haemospermia 6.8.1 Definition and classification 6.8.2 Pathophysiology and risk factors 6.8.3 Investigations 6.8.4 Disease management 6.9 Recommendations for the management of recurrent haemospermia

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7. LOW SEXUAL DESIRE AND MALE HYPOACTIVE SEXUAL DESIRE DISORDER 7.1 Definition, classification and epidemiology 7.2 Pathophysiology and risk factors 7.2.1 Psychological aspects 7.2.2 Biological aspects 7.2.3 Risk factors 7.3 Diagnostic work-up 7.3.1 Assessment questionnaires 7.3.2 Physical examination and investigations 7.4 Disease management 7.4.1 Psychological intervention 7.4.2 Pharmacotherapy 7.5 Recommendations for the treatment of low sexual desire

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8. PENILE CURVATURE 8.1 Congenital penile curvature 8.1.1 Epidemiology/aetiology/pathophysiology 8.1.2 Diagnostic evaluation 8.1.3 Disease management 8.1.4 Summary of evidence for congenital penile curvature 8.1.5 Recommendation for the treatment congenital penile curvature 8.2 Peyronie’s Disease 8.2.1 Epidemiology/aetiology/pathophysiology 8.2.1.1 Epidemiology 8.2.1.2 Aetiology 8.2.1.3 Risk factors 8.2.1.4 Pathophysiology 8.2.1.5 Summary of evidence on epidemiology/aetiology/pathophysiology of Peyronie’s disease 8.2.2 Diagnostic evaluation 8.2.2.1 Summary of evidence for diagnosis of Peyronie’s disease 8.2.2.2 Recommendations for diagnosis of Peyronie’s disease 8.2.3 Disease management 8.2.3.1 Conservative treatment 8.2.3.1.1 Oral treatment 8.2.3.1.2 Intralesional treatment 8.2.3.1.3 Topical treatments 8.2.3.1.4 Multimodal treatment 8.2.3.1.5 Summary of evidence for conservative treatment of Peyronie’s disease 8.2.3.1.6 Recommendations for non-operative treatment of Peyronie’s disease 8.2.3.2 Surgical treatment 8.2.3.2.1 Tunical shortening procedures 8.2.3.2.2 Tunical lengthening procedures 8.2.3.2.3 Penile prosthesis 8.2.3.2.4 Summary of evidence for non-operative treatment of Peyronie’s disease 8.2.3.2.5 Recommendations for surgical treatment of penile curvature 8.2.3.3 Treatment algorithm

88 88 88 88 88 88 88 88 88 88 88 90 90

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91 91 92 92 92 92 93 93 95 98 98 99 99 100 101 103 103 104 104

5

9. PRIAPISM 9.1 Ischaemic (Low-Flow or Veno-Occlusive) Priapism 9.1.1 Epidemiology, aetiology, pathophysiology and Diagnosis 9.1.1.1 Summary of evidence on the epidemiology, aetiology and pathophysiology of ischaemic priapism 9.1.2 Diagnostic evaluation 9.1.2.1 History 9.1.2.2 Physical examination 9.1.2.3 Laboratory testing 9.1.2.4 Penile imaging 9.1.2.5 Recommendations for the diagnosis of ischaemic priapism 9.1.3 Disease management 9.1.3.1 Medical Management 9.1.3.1.1 First-line treatments 9.1.3.1.2 Penile anaesthesia/analgesia 9.1.3.1.3 Aspiration ± irrigation with 0.9% w/v saline solution 9.1.3.1.4 Aspiration ± irrigation with 0.9% w/v saline solution in combination with intracavernous injection of pharmacological agents. 9.1.3.2 Surgical management 9.1.3.2.1 Second-line treatments 9.1.3.2.1.1 Penile shunt surgery 9.1.4 Summary of evidence for treatment of ischaemic priapism 9.1.5 Recommendations for the treatment of ischaemic priapism 9.2 Priapism in Special Situations 9.2.1 Stuttering (recurrent or intermittent) priapism 9.2.1.1 Epidemiology/aetiology/pathophysiology 9.2.1.1.1 Summary of evidence on the epidemiology, aetiology and pathophysiology of stuttering priapism 9.2.1.2 Classification 9.2.1.3 Diagnostic evaluation 9.2.1.3.1 History 9.2.1.3.2 Physical examination 9.2.1.3.3 Laboratory testing 9.2.1.3.4 Penile imaging 9.2.1.4 Disease management 9.2.1.4.1 α-Adrenergic agonists 9.2.1.4.2 Hormonal manipulations of circulating testosterone 9.2.1.4.3 Digoxin 9.2.1.4.4 Terbutaline 9.2.1.4.5 Gabapentin 9.2.1.4.6 Baclofen 9.2.1.4.7 Hydroxyurea 9.2.1.4.8 Phosphodiesterase type 5 inhibitors 9.2.1.4.9 Intracavernosal injections 9.2.1.4.10 Penile prosthesis 9.2.1.5 Summary of evidence for treatment of stuttering priapism 9.2.1.6 Recommendations for treatment of stuttering priapism 9.2.1.7 Follow-up 9.2.2 Priapism in children 9.3 Non-ischaemic (high-flow or arterial) priapism 9.3.1 Epidemiology/aetiology/pathophysiology 9.3.1.1 Summary of evidence on the epidemiology, aetiology and pathophysiology of arterial priapism 9.3.2 Classification 9.3.3 Diagnostic evaluation 9.3.3.1 History 9.3.3.2 Physical examination 9.3.3.3 Laboratory testing 9.3.3.4 Penile imaging

6

106 106 106 108 109 109 109 109 110 110 111 111 112 112 112

113 115 115 115 119 119 120 120 120 120 121 121 121 121 121 121 121 121 121 122 122 122 122 122 122 123 123 123 123 123 123 124 124 124 124 125 125 125 125 125

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9.3.3.5 Recommendations for the diagnosis of non-ischaemic priapism 9.3.4 Disease management 9.3.4.1 Conservative management 9.3.4.2 Selective arterial embolisation 9.3.4.3 Surgical management 9.3.4.4 Summary of evidence for the treatment of arterial priapism 9.3.4.5 Recommendations for the treatment of arterial priapism 9.3.4.6 High-flow priapism in children 9.3.4.7 Follow-up 9.4 Controversies and future areas of focus in the management of priapism

125 125 126 126 126 126 127 127 127 127

10. MALE INFERTILITY 10.1 Definition and classification 10.2 Epidemiology/aetiology/pathophysiology/risk factors 10.2.1 Introduction 10.2.2 Recommendations on epidemiology and aetiology 10.3 Diagnostic work-up 10.3.1 Medical/reproductive history and physical examination 10.3.1.1 Medical and reproductive history 10.3.1.2 Physical examination 10.3.2 Semen analysis 10.3.3 Measurement of sperm DNA Fragmentation Index (DFI) 10.3.4 Hormonal determinations 10.3.5 Genetic testing 10.3.5.1 Chromosomal abnormalities 10.3.5.1.1 Sex chromosome abnormalities (Klinefelter syndrome and variants [47,XXY; 46,XY/47, XX mosaicism]) 10.3.5.1.2 Autosomal abnormalities 10.3.5.2 Cystic fibrosis gene mutations 10.3.5.2.1 Unilateral or bilateral absence/abnormality of the vas and renal anomalies 10.3.5.3 Y microdeletions - partial and complete 10.3.5.3.1 Clinical implications of Y microdeletions 10.3.5.3.1.1 Testing for Y microdeletions 10.3.5.3.1.2 Genetic counselling for AZF deletions 10.3.5.3.1.3 Y-chromosome: ‘gr/gr’ deletion 10.3.5.3.1.4 Autosomal defects with severe phenotypic abnormalities and infertility 10.3.5.4 Sperm chromosomal abnormalities 10.3.5.5 Measurement of Oxidative Stress 10.3.5.6 Outcomes from assisted reproductive technology and long-term health implications to the male and offspring 10.3.6 Imaging in the infertile men 10.3.6.1 Scrotal US 10.3.6.1.1 Testicular neoplasms 10.3.6.1.2 Varicocele 10.3.6.1.3 Other 10.3.6.2 Transrectal US 10.3.7 Recommendations for the diagnostic work-up of male infertility 10.4 Special Conditions and Relevant Clinical Entities 10.4.1 Cryptorchidism 10.4.1.1 Classification 10.4.1.1.1 Aetiology and pathophysiology 10.4.1.1.2 Pathophysiological effects in maldescended testes 10.4.1.1.2.1 Degeneration of germ cells 10.4.1.1.2.2 Relationship with fertility 10.4.1.1.2.3 Germ cell tumours 10.4.1.2 Disease management 10.4.1.2.1 Hormonal treatment 10.4.1.2.2 Surgical treatment

128 128 128 128 129 129 129 129 130 130 131 131 132 132

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132 133 133 134 134 134 134 135 135 135 135 135 136 136 136 136 137 137 137 138 139 139 139 139 139 139 139 139 140 140 140

7

10.4.1.3 Summary of evidence recommendations for cryptorchidism 10.4.2 Germ cell malignancy and male infertility 10.4.2.1 Testicular germ cell cancer and reproductive function 10.4.2.2 Testicular microcalcification (TM) 10.4.2.3 Recommendations for germ cell malignancy and testicular microcalcification 10.4.3 Varicocele 10.4.3.1 Classification 10.4.3.2 Diagnostic evaluation 10.4.3.3 Basic considerations 10.4.3.3.1 Varicocele and fertility 10.4.3.3.2 Varicocelectomy 10.4.3.3.3 Prophylactic varicocelectomy 10.4.3.3.4 Varicocelectomy for assisted reproductive technology and raised DNA fragmentation 10.4.3.4 Disease management 10.4.3.5 Summary of evidence and recommendations for varicocele 10.4.4 Male accessory gland infections and infertility 10.4.4.1 Introduction 10.4.4.2 Diagnostic evaluation 10.4.4.2.1 Semen analysis 10.4.4.2.2 Microbiological findings 10.4.4.2.3 White blood cells 10.4.4.2.4 Sperm quality 10.4.4.2.5 Seminal plasma alterations 10.4.4.2.6 Glandular secretory dysfunction 10.4.4.2.7 Reactive oxygen species 10.4.4.2.8 Disease management 10.4.4.3 Epididymitis 10.4.4.3.1 Diagnostic evaluation 10.4.4.3.1.1 Ejaculate analysis 10.4.4.3.1.2 Disease management 10.4.4.4 Summary of evidence and recommendation for male accessory gland infections 10.5 Non-Invasive Male Infertility Management 10.5.1 Idiopathic male infertility and oligo-astheno-terato-zoospermia 10.5.2 Empirical treatments 10.5.2.1 Life-style 10.5.2.1.1 Weight loss 10.5.2.1.2 Physical activity 10.5.2.1.3 Smoking 10.5.2.1.4 Alcohol consumption 10.5.2.2 Antioxidant treatment 10.5.2.3 Selective oestrogen receptor modulators 10.5.2.4 Aromatase inhibitors 10.5.3 Hormonal therapy 10.5.3.1 Gonadotrophins 10.5.3.2 Secondary hypogonadism 10.5.3.2.1 Pre-Pubertal-Onset 10.5.3.2.2 Post-Pubertal Onset Secondary 10.5.3.3 Primary Hypogonadism 10.5.3.4 Idiopathic Male Factor Infertility 10.5.3.5 Anabolic Steroid Abuse 10.5.3.6 Recommendations for treatment of male infertility with hormonal therapy 10.6 Invasive Male Infertility Management 10.6.1 Obstructive azoospermia 10.6.1.1 Classification of obstructive azoospermia 10.6.1.1.1 Intratesticular obstruction 10.6.1.1.2 Epididymal obstruction

8

140 140 141 142 143 143 143 143 143 143 144 144 145 145 147 147 147 147 147 147 148 148 148 148 148 149 149 149 149 149 149 150 150 150 150 150 150 150 150 150 151 151 151 151 152 152 152 153 153 153 153 153 153 154 154 154

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10.6.1.1.3 Vas deferens obstruction 10.6.1.1.4 Ejaculatory duct obstruction 10.6.1.1.4.1 Functional obstruction of the distal seminal ducts 10.6.1.2 Diagnostic evaluation 10.6.1.2.1 Clinical history 10.6.1.2.2 Clinical examination 10.6.1.2.3 Semen analysis 10.6.1.2.4 Hormone levels 10.6.1.2.5 Genetic Testing 10.6.1.2.6 Testicular biopsy 10.6.1.3 Disease management 10.6.1.3.1 Intratesticular obstruction 10.6.1.3.2 Epididymal obstruction 10.6.1.3.3 Vas deferens obstruction after vasectomy 10.6.1.3.4 Vas deferens obstruction at the inguinal level 10.6.1.3.5 Ejaculatory duct obstruction 10.6.1.4 Summary of evidence and recommendations for obstructive azoospermia 10.6.2 Non-obstructive azoospermia 10.6.2.1 Investigation of non-obstructive azoospermia 10.6.2.2 Surgery for non-obstructive azoospermia 10.6.2.3 3 Indications and techniques of sperm retrieval 10.6.2.4 Recommendations for Non-Obstructive Azoospermia 10.7 Assisted Reproductive Technologies 10.7.1 Types of assisted reproductive technology 10.7.1.1 Intra-uterine insemination (IUI) 10.7.1.2 In vitro fertilisation (IVF) 10.7.1.3 Intracytoplasmic sperm injection 10.7.1.4 Testicular sperm in men with raised DNA fragmentation in ejaculated sperm 10.7.1.5 Intra-cytoplasmic morphologically selected sperm injection 10.7.1.6 Physiological ICSI (PICSI) technique: a selection based on membrane maturity of sperm 10.7.1.7 Magnetic-activated cell sorting (MACS) 10.7.2 Safety

164 164 164

11.

LATE EFFECTS, SURVIVORSHIP AND MEN’S HEALTH

165

12.

REFERENCES

166

13.

CONFLICT OF INTEREST

269

14.

CITATION INFORMATION

270



APPENDICES

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154 154 154 155 155 155 155 155 155 155 155 155 155 156 156 156 156 157 157 157 157 160 161 161 161 161 162 163 163

9

1.

INTRODUCTION

1.1

Aims and Objectives

The European Association of Urology (EAU) Sexual and Reproductive Health Guidelines aim to provide a comprehensive overview of the medical aspects relating to sexual and reproductive health in adult men. These Guidelines cover the former EAU Guidelines on Male Sexual Dysfunction, Male Infertility and Male Hypogonadism. It must be emphasised that guidelines present the best evidence available to the experts. However following guideline recommendations will not necessarily result in the best outcome. Guidelines can never replace clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions - while taking personal values and preferences/individual circumstances of patients into account. Guidelines are not mandates and do not purport to be a legal standard of care.

1.2

Panel composition

The EAU Sexual and Reproductive Health Guidelines Panel consists of an international multi-disciplinary group of urologists, endocrinologists and a psychologist. All experts involved in the production of this document have submitted potential conflict of interest statements which can be viewed on the EAU website: http://www.uroweb.org/guideline/sexualandreproductivehealth/.

1.3

Available Publications

Alongside the full text version, a quick reference document (Pocket Guidelines) is available in print and as an app for iOS and android devices. These are abridged versions that may require consultation together with the full text version. All documents can be viewed through the EAU website: http://www.uroweb.org/guideline/ sexualandreproductivehealth/.

1.4

Publication History

This document is a further update of the 2020 Guidelines which already included a comprehensive update of the 2018 versions of Male Sexual Dysfunction, Male Infertility and Male Hypogonadism guidelines, along with several new topics. Additional sections will be added in the coming years to address male contraception, vasectomy, and penile cosmetic surgery, which have not been previously addressed.

1.5

Changes in the Guideline for 2021

The results of ongoing and new systematic reviews have been included in the 2021 update of the Sexual and Reproductive Health Guidelines. Systematic reviews undertaken in 2020 were: • What is the effectiveness of non-surgical therapies in the treatment of ischaemic priapism in patients with sickle cell disease? • What is the effectiveness of non-surgical therapies in the management of priapism in patients without sickle cell disease? • What is the effectiveness of surgical therapies in the treatment of priapism?

2.

METHODOLOGY

2.1

Methods

For the 2021 Sexual and Reproductive Health Guidelines, further new evidence has been identified, collated and appraised through a structured assessment of the literature. For each recommendation within the Guidelines there is an accompanying online strength rating form; the basis of which is a modified Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology [1, 2]. Each strength rating form addresses several key elements namely: 1. the overall quality of the evidence which exists for the recommendation, references used in this text are graded according to a classification system modified from the Oxford Centre for Evidence-Based Medicine Levels of Evidence [3]; 2. the magnitude of the effect (individual or combined effects); 3. the certainty of the results (precision, consistency, heterogeneity and other statistical or study-related factors); 4. the balance between desirable and undesirable outcomes; 5. the impact of patient values and preferences on the intervention; 6. the certainty of those patient values and preferences.

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SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021

These key elements are the basis that panels use to define the strength rating of each recommendation. The strength of each recommendation is represented by the term ‘strong’ or ‘weak’ [4]. The strength of each recommendation is determined by the balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including certainty of estimates), and nature and variability of patient values and preferences. Additional information can be found in the general Methodology section of this print, and online at the European Association of Urology (EAU) website: http://www.uroweb.org/guideline/. A list of associations endorsing the EAU Guidelines can also be viewed online at this address.

2.2

Review

The existing sections of the Sexual and Reproductive Health Guidelines were peer reviewed prior to publication in 2020. The new section for priapism was reviewed prior to publication in 2021.

2.3

Future goals

The results of ongoing and new systematic reviews will be included in the 2022 update of the Sexual and Reproductive Health Guidelines. Systematic reviews planned for 2021 are: • Penile cosmetic surgery; • Vasectomy.

3.

MALE HYPOGONADISM

3.1

Epidemiology and prevalence of male hypogonadism

Male hypogonadism is associated with decreased testicular function, with decreased production of androgens and/or impaired sperm production [5]. This is caused by poor testicular function or as a result of inadequate stimulation of the testes by the hypothalamic-pituitary axis. Several congenital or acquired disorders causing impaired action of androgens are also described [5]. Hypogonadism may adversely affect multiple organ functions and quality of life (QoL) [6]. Late-onset hypogonadism (LOH) is a clinical condition in ageing men, which, by definition, must comprise both persistent specific symptoms and biochemical evidence of testosterone deficiency [5, 7]. Late-onset hypogonadism is frequently diagnosed in the absence of an identifiable classical cause of hypogonadism, which becomes more prevalent with age, usually occurring, but not exclusively, in men aged > 40 years. Male hypogonadism has also been called Testosterone Deficiency. The Panel has agreed to use the term Male Hypogonadism, which may better reflect and explain the underlying pathophysiology. Likewise, the Panel has further agreed to continue with the term testosterone therapy. The present Guidelines specifically address the management of adult male hypogonadism also called LOH. Some insights related to congenital or pre-pubertal hypogonadism are also provided and summarised. The prevalence of hypogonadism increases with age and the major causes are central obesity, co-morbidity (e.g., diabetes) and overall poor health [8]. In healthy ageing men, there is only a small gradual decline in testosterone; up to the age of 80 years, age accounts for a low percentage of hypogonadism [8]. In men aged 40-79 years, the incidence of symptomatic hypogonadism varies between 2.1-5.7% [9-11]. The incidence of hypogonadism has been reported to be 12.3 and 11.7 cases per 1,000 people per year [9, 12]. There is a high prevalence of hypogonadism within specific populations, including patients with type 2 diabetes (T2DM), metabolic syndrome (MetS), obesity, cardiovascular disease (CVD), chronic obstructive pulmonary disease, renal disease and cancer [11]. Low testosterone levels are common in men with T2DM [13] and a high prevalence of hypogonadism (42%) has been reported in T2DM patients [14]. Klinefelter syndrome, a trisomy associated with a 47,XXY karyotype, is the most prevalent genetic cause of primary hypogonadism (hypergonadotropic hypogonadism), with a global prevalence of 1/500-1,000 live male births [15-17]. However, < 50% of individuals with Klinefelter syndrome are diagnosed in their lifetime [18]. 3.1.1 Body Composition and Metabolic Profile Low testosterone levels are common in men with obesity. Male hypogonadism is associated with a greater percentage of fat mass and a lesser lean mass compared to men with adequate testosterone levels [19]. There is much evidence that low testosterone level is strongly associated with increased visceral adiposity, but it also leads to lipid deposition in the liver and muscle and is associated with atherosclerosis [19]. In vitro studies have suggested that hypogonadism impairs glucose and triglyceride uptake into subcutaneous fat depots [19]. This enhances the uptake of glucose and triglycerides into ectopic fat depots.

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11

Testosterone therapy has been associated with a reduced percentage of body fat and increase of lean body mass [20]. Data from a registry study have suggested that over a period of 8 years, testosterone therapy with long-acting intramuscular testosterone undecanoate was associated with a substantial but gradual loss of weight along with a reduction in waist circumference [21]. Testosterone also reduces liver fat content and muscle fat storage [19]. 3.1.2 Metabolic Syndrome/Type 2 Diabetes Metabolic Syndrome (MetS) is characterised by several specific components, including increased waist circumference, dyslipidaemia, hypertension, and impaired glucose tolerance. Hypogonadism is associated with central obesity, hyperglycaemia, insulin resistance and dyslipidaemia [low high-density lipoprotein (HDL) cholesterol, raised total and low-density lipoprotein (LDL) cholesterol and triglycerides], hypertension and predisposition to T2DM, which are all components of MetS [22]. Several randomised controlled trials (RCTs) have shown that testosterone therapy might improve insulin resistance and hyperglycaemia and lower cholesterol and LDL-cholesterol [23-27]. Testosterone therapy in hypogonadal T2DM improved glycaemic control in some RCTs and registry trials; however, there is no conclusive evidence from RCTs and meta-analyses [24, 28, 29]. A recent large placebo-controlled RCT, including 1,007 patients with impaired glucose tolerance or newly-diagnosed T2DM and total testosterone < 14 nmol/L, showed that testosterone therapy for 2 years reduced the proportion of patients with T2DM regardless of a lifestyle programme [30]. Similarly, a previously published registry study reported that testosterone therapy was associated in time with remission of T2DM [28]. HDL-cholesterol may decrease, remain unchanged or increase with testosterone therapy. Testosterone therapy in men with MetS and low testosterone has been shown to reduce mortality compared to that in untreated men [31, 32], although no conclusive evidence is available. Erectile dysfunction (ED) is common in men with MetS and T2DM (up to 70% of patients). The causes of ED are multi-factorial and 30% of men with ED have co-existing testosterone-deficiency hypogonadism. Some evidence has suggested that for patients with T2DM this is only found in men with clearly reduced testosterone levels (< 8 nmol/L or 2.31 ng/mL) [33]. From a pathophysiological point of view, it has been reported that this is because ED is predominantly caused by vascular and neuropathic disease, and therefore not likely in men who do not have established vascular disease. Therefore, men presenting with ED should be screened for MetS. Likewise, patients with ED and diabetes may be offered testosterone measurement. Placebo-controlled RCTs of testosterone therapy in T2DM have demonstrated improved sexual desire and satisfaction, but not erectile function [24, 33]. The presence of multiple comorbidity in this group of patients may confound the response to testosterone therapy alone. In a long-term registry study in men with T2DM, parenteral testosterone undecanoate therapy led to one third of patients entering remission from diabetes during 11 years’ follow-up [34]. A large 2-year RCT of testosterone undecanoate vs. placebo showed that testosterone therapy significantly decreased progression of 999 men with low testosterone (< 14 nmol/L) from pre-diabetes to overt T2DM [30].

3.2

Physiology of testosterone production

The pituitary gland regulates testicular activity through secretion of luteinising hormone (LH), which regulates testosterone production in Leydig cells and follicle-stimulating hormone (FSH), which mainly controls sperm production in seminiferous tubules [35, 36]. The production and secretion of gonadotropins is stimulated by hypothalamic gonadotropin releasing hormone (GnRH) and inhibited by negative feedback mediated by the central action of sex steroids and inhibin B (Figure 1) [35, 36]. Gonadotropin releasing hormone is secreted in a pulsatile manner and negatively controlled by the activity of hypothalamic neurons, including corticotrophin-releasing hormone (CRH) and β endorphin neurons [35, 36]. Conversely, kisspeptin-1 (Kiss-1) neurons, neurokinin-B and tachykinin-3 are involved in GnRH stimulation. Leptin is involved in activation of Kiss-1 signalling [37]. About 25 mg of testosterone is present in the normal testes, and, on average, 5-10 mg of testosterone are secreted daily [35, 36]. The testes also produce lesser amounts of other androgens, such as androstenedione and dihydrotestosterone (DHT). A small amount of extra-gonadal testosterone is derived from circulating weak adrenal androgen precursor dehydroepiandrosterone (DHEA), although its specific contribution to daily testosterone production is limited in men [38, 39]. In physiological terms, DHT formation accounts for 6-8% of testosterone metabolism, and the ratio of plasma testosterone/DHT is approximately 1:20 [35, 36]. Finally, testosterone and its precursor, Δ4 androstenedione, can be aromatised through P450 aromatase to other bioactive metabolites, such as oestrone (E1) and 17-β-oestradiol (E2), with a daily production of ~45 μg [35, 36]. Leydig cells, can also directly produce and release into the bloodstream small amounts of oestrogens, with a daily production rate of 5-10 μg (up to 20% of circulating oestrogens) [40].

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SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021

Figure 1: Physiology of testosterone production

HYPOTHALAMUS GnRH

Kisspeptin Neurokinin B Tachykinin-3

+

CRH β endorphin -

+

PITUITARY LH

FSH -

-

T, E2 DHT

LH

Inhibin B

TESTES

+

Leydig cells

FSH

+ Seroli cells

GnRH = gonadotropin releasing hormone; LH = luteinising hormone; FSH = follicle-stimulating hormone; T = testosterone; E2 = 7-β-estradiol; DHT = dehydroepiandrosterone; CRH = corticotrophin releasing hormone. 3.2.1 Circulation and transport of testosterone In healthy men, 60-70% of circulating testosterone is bound to the high-affinity sex-hormone-binding globulin (SHBG), a protein produced by the liver, which prevents its bound testosterone sub-fraction from biological action. The remaining circulating testosterone binds to lower affinity, high-capacity binding proteins, (albumin, α-1 acid glycoprotein and corticosteroid-binding protein), and only 1-2% of testosterone remains nonprotein bound [41]. There is a general agreement that testosterone bound to lower-affinity proteins can easily dissociate in the capillary bed of many organs, accounting for so-called ‘bioavailable’ testosterone [41]. It is important to recognise that several clinical conditions and ageing itself can modify SHBG levels, thus altering circulating total testosterone levels (Table 1). Therefore, if not recognised, these factors could lead to an incorrect estimation of male androgen status. Therefore, when indicated (Table 1), SHBG should be tested and free testosterone calculated.

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13

Table 1:

Main factors associated with an increase or reduction of SHBG circulating levels

SHBG increase

SHBG decrease

• • • • • • • • • • • • • •

Drugs: anticonvulsants, oestrogens, thyroid hormone Hyperthyroidism Hepatic disease Ageing Smoking AIDS/HIV Drugs: growth hormone (GH), glucocorticoids, testosterone, anabolic androgenic steroids Hypothyroidism Obesity Acromegaly [42] Cushing’s disease Insulin resistance (MetS/T2DM) Non-alcoholic fatty liver disease (NAFLD), Nephrotic syndrome

3.2.2 Androgen receptor Testosterone and DHT exert their biological action through activation of a specific nuclear receptor. The androgen receptor (AR) gene is localised on the X chromosome (Xq11–12), encoded in eight exons [43]. Exon 1 includes two polymorphic trinucleotide repeat segments encoding polyglutamine (CAG) and polyglycine (GGN) tracts in the N-terminal transactivation domain of its protein. Activity of the AR is inversely associated with the length of the CAG repeat chains [43]. However, the specific role of AR CAG repeat number in relation to hypogonadal symptoms or to clinical management of testosterone deficiency remains unclear [44, 45]. A RCT has shown that a higher CAG repeat number is positively associated with a change in fasting insulin, triglyceride and diastolic blood pressure, demonstrating the more sensitive the receptor, the greater the benefit [46].

3.3

Role of testosterone in male sexual and reproductive health

3.3.1 Sexual development and maturation Testosterone production in the foetal testis starts between the eighth and ninth week of gestation after the expression of the SRY gene, which regulates organisation of the undifferentiated gonadal ridge into the testis [47]. During the first trimester, the testes drive the virilisation of internal and external genitalia through placental human chorionic gonadotropin (hCG)-stimulated androgen secretion by Leydig cells. During foetal life, testosterone mainly controls the differentiation of internal genitalia and testicular descent (regression of gubernaculum testis), whereas DHT is mainly involved in the development of the external male genitalia [48]. During puberty, reactivation of the hypothalamus–pituitary-gonadal (HPG) axis allows the development of secondary sexual characteristics, spermatogenesis maturation and, along with the contribution of other hormonal axes, completion of the adolescent growth spurt [5, 49]. Clinical models of aromatase deficiency and oestrogen receptor insensitivity have demonstrated that testosterone conversion to oestradiol is essential for epiphyseal closure and growth arrest [50]. 3.3.2 Sexual function Testosterone is involved in the regulation of all steps of the male sexual response. Sexual thoughts and motivations are universally accepted as the most testosterone-dependent aspects of male sexual behaviour [20]. The European Male Aging Study (EMAS), a population-based survey including 3,369 subjects aged 40-79 years from eight European countries, showed that sexual symptoms, particularly impairment of sexual desire, ED and decreased frequency of morning erections, were the most specific symptoms associated with age-depended decline of testosterone [10]. Similar findings were reported in patients consulting for sexual dysfunctions [51]. Accordingly, several brain areas, including the amygdala, medial preoptic area, paraventricular nucleus of the hypothalamus, and peri-aqueductal grey matter express androgen receptors [51, 52]. Experimental and clinical studies have both documented that testosterone plays a crucial role in regulating penile function. In particular, testosterone controls the structural integrity necessary for penile erection, as well as several enzymatic activities within the corpus cavernosum, including a positive action on nitric oxide (NO) formation and a negative influence on the activity of the Ras homolog gene family member A/Rho-associated kinase (RhoA/ROCK) pathways [51, 53]. Testosterone is also involved in penile adrenergic response and cavernous smooth muscle cell turnover [51, 53]. Although some authors have suggested a positive role for testosterone in regulating penile phosphodiesterase 5 (PDE5) expression and activity, others have shown an inhibitory role of oestrogens on this pathway [51, 54].

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SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021

More limited evidence has indicated a possible role of testosterone in regulating ejaculation, acting either at the central or peripheral level. Androgen receptors are expressed in several central spinal and superspinal areas involved in the control of the ejaculatory reflex [55]. Additionally, the male genital tract expresses NO-PDE5 and RhoA/ROCK pathways, which are modulated by testosterone [55].

3.4

Classification and causes of male hypogonadism

Male hypogonadism can be classified according to the origin of the underlying problem into primary, if a consequence of testicular dysfunction, or secondary, if due to a pituitary or hypothalamic dysfunction (Table 2). Primary hypogonadism is also called hypergonadotropic hypogonadism, since the pituitary tries to compensate for testicular dysfunction by increasing central stimulation. Conversely, in secondary hypogonadism the testes are inadequately stimulated by gonadotropins, usually with inappropriately normal or reduced gonadotropin levels [5, 36]. A compensated or subclinical form of hypogonadism, characterised by normal testosterone serum levels and elevated LH production, has also been reported [56]; the clinical significance of the latter condition is unclear [56-58]. Finally, hypogonadism can also result from several conditions leading to reduced sensitivity/insensitivity to testosterone and its metabolites [5, 36] (Table 2). This classification, based on the aetiology of hypogonadism, allows clinicians to adequately select appropriate treatment. In patients with secondary hypogonadism, both fertility and testosterone normalisation can be theoretically achieved with adequate treatment whereas in primary hypogonadism only testosterone therapy can be considered, which impairs fertility due to suppression of the HGP axis [5, 36] (Table 2). However, it should also be recognised that symptoms and signs of hypogonadism can be similarly independent of the site of origin of the disease. Conversely, the age of onset of hypogonadism can influence the clinical phenotype [37]. Accordingly, when the problem starts early, such as during foetal life, clinical phenotype can span from an almost complete female phenotype (e.g., complete androgen insensitivity or enzymatic defects blocking androgen synthesis) to various defects in virilisation. In the case of a pre- or peri-pubertal appearance of hypogonadism due to a milder central (isolated hypogonadotropic hypogonadism) or a peripheral defect (such as in Klinefelter’s syndrome), there might be delayed puberty with an overall eunochoid phenotype. Finally, when hypogonadism develops after puberty and especially with ageing (i.e., LOH; see below), symptoms can be mild, and often confused the with ageing process per se [5, 37]. In 2017, Grossmann and Matsumoto suggested a new classification of adult male hypogonadism, distinguishing functional versus organic hypogonadism [59]. Accordingly, organic hypogonadism is characterised by any proven pathology affecting the HPG axis and should be treated with conventional medication (i.e., gonadotropins or testosterone therapy). Conversely, functional hypogonadism is based on the absence of any recognised organic alterations in the HPG axis and should be treated first by resolving or improving the associated comorbidity. These Guidelines refer to the validated international classification of adult male hypogonadism. Table 2: Classification of male hypogonadism PRIMARY HYPOGONADISM (hypergonadotropic hypogonadism) Congenital or developmental disorders Common causes Uncommon causes Klinefelter syndrome - Rare chromosomal abnormalities - XX male syndrome - 47 XYY syndrome - 48 XXYY syndrome - 21 Trisomy (Down syndrome) - Noonan syndrome - Autosomal translocations1 - Defects of testosterone biosynthesis - CAH (testicular adrenal rest tumours) - Disorders of sex development (gonadal dysgenesis) - LHR gene mutations - Myotonic dystrophy (including type I and II) - Uncorrected cryptorchidism (including INSL3 and LGR8 mutations) - Bilateral congenital anorchia - Sickle cell disease - Adreno-leukodystrophy

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Acquired disorders Drug-induced Localised problems - Bilateral surgical castration or trauma - Chemotherapy agents - Testicular irradiation Alkylating agents - Orchitis (including mumps orchitis) Methotrexate - Testosterone synthesis inhibitors - Autoimmune testicular failure - Testicular Torsion • Ketoconazole - Alcohol/Cirrhosis • Aminoglutethimide - Environmental Toxins • Mitotane • Metyrapon Systemic diseases/conditions with hypothalamus/pituitary impact - Malignancies - Chronic systemic diseases* - Lymphoma - Chronic organ failure* - Testis cancer - Glucocorticoid excess (Cushing - Spinal cord injury syndrome)* - Vasculitis - Aging* - Infiltrative diseases (amyloidosis; leukaemia) - HIV SECONDARY HYPOGONADISM (hypogonadotropic hypogonadism) Congenital or developmental disorders Common causes Uncommon causes - Haemochromatosis* - Combined hormone pituitary deficiency - Idiopathic hypogonadotropic hypogonadism - (IHH) with variants: - Normosmic IHH - Kallmann syndrome - Isolated LH β gene mutations - Prader-Willi Syndrome Acquired disorders Drug-induced Localised problems - Traumatic brain injury - Oestrogens - Pituitary neoplasm (micro/macro-adenomas) - Testosterone or androgenic - Hypothalamus tumours anabolic steroids - Pituitary stalk diseases - Progestogens (including - Iatrogenic cyproterone acetate) - Surgical hypophisectomy - Hyperprolactinaemia-induced - Pituitary or cranial irradiation drugs - Inflammatory and infectious diseases - Opiates - Lymphocytic hypophysitis - GnRH agonist or antagonist - Pituitary infections - Glucocorticoids - Granulomatous lesions - Sarcoidosis - Wegener’s granulomatosis - Other granulomatosis - Encephalitis - Langerhans’ histiocytosis - Hyperprolactinaemia as a consequence of localised problems (hypothalamus-pituitary mass) Systemic diseases/conditions impacting the hypothalamus/pituitary - Spinal cord injury - Chronic systemic diseases* - Transfusion-related iron overload (β-thalassemia) - Metabolic diseases - HIV infection - Chronic organ failure - Chronic Inflammatory Arthritis - Glucocorticoid excess (Cushing syndrome)* - Eating disorders* - Endurance exercise - Acute and critical illness - Ageing*

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ANDROGEN RESISTANCE/DECREASED TESTOSTERONE BIOACTIVITY Congenital or developmental disorders - Aromatase deficiency - Kennedy diseases (spinal and bulbar muscular atrophy) and other extensions of CAG repeats - Partial or complete androgen insensitivity - 5α reductase type II (5αR) deficiency Acquired disorders Drug-induced Localised problems - Coeliac disease - Drug-induced AR blockage - Steroidal antiandrogen - Cyproterone acetate - Spironolactone - Non-steroidal antiandrogen - Flutamide - Bicalutamide - Nilutamide -D  rug-induced 5α reductase (5αR) activity blockade - Finasteride - Dutasteride - Drug-induced ER blockade - Clomiphene - Tamoxifen - Raloxifene -D  rug-induced aromatase activity blockade - Letrozole - Anastrazole - Exemestane - Increased SHBG * Conditions acting and central and peripheral levels resulting in either primary and secondary hypogonadism. Different autosomal translocations can cause rare cases of hypogonadism and infertility.

1

3.5

Late-onset hypogonadism

Testosterone production declines with ageing. The EMAS study reported a 0.4% per annum (log hormoneage) decrease in total testosterone and a 1.3% per annum decline in free testosterone (fT) [8]. Late onset hypogonadism is the term frequently used to describe this phenomenon and the detection of hypogonadism in adulthood, in particular. Evidence has documented that several associated diseases and chronic co-morbidity can interfere with the HPG axis leading to development of primary hypogonadism or, more frequently, secondary hypogonadism in adulthood, thus significantly influencing the physiological age-dependent decline of testosterone. By combining the data from three different waves of the Massachusetts Male Aging Study (MMAS), a population-based, observational study including 1,709 men aged 40–70 years, showed that associated comorbidity and obesity significantly decreased, whereas smoking tended to increase total, free and bio-available testosterone concentrations [60]. Similarly, data derived from the EMAS study confirm these findings [8, 57]. Based upon these data and other evidence, the concept of functional and organic hypogonadism has been recently introduced [59]. The diagnosis of functional hypogonadism is based on the exclusion of a classical (organic) aetiology. The main causes of functional hypogonadism are obesity, co-morbidity and ageing with the first two accounting for most cases. Inflammatory cytokines released in chronic inflammation, and adipocytokines and oestradiol in obesity, can suppress the HPG axis. The role of ageing up to age 80 years seems relatively small [59]. Considering that suppression of HPG axis activity is functional, and potentially reversible by empiric measures, such as weight loss, the need for testosterone therapy has been questioned [59]. 3.5.1 Diagnostic evaluation The phenotype of the hypogonadal patient appears independent of the aetiology causing the problem, but is more often affected by the age of onset of hypogonadism. When androgen deficiency is complete and develops during foetal life, symptoms can be dramatic, spanning from an almost complete female phenotype (complete androgen insensitivity or enzymatic defects blocking androgen synthesis) to various defects in virilisation and ambiguous genitalia (micropenis, hypospadias and cryptorchidism) [5, 36]. Delay in puberty

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with an overall eunochoidal phenotype (scant body hair, high-pitched voice and small testes, penis and prostate) is typical of defects manifesting over the pre- or peri-pubertal period due to milder central (isolated HH) or peripheral defects (such as in Klinefelter syndrome) [5, 36]. When hypogonadism occurs in adulthood, especially functional hypogonadism, symptoms can often be mild, difficult to recognise and frequently confused with the ageing process [5, 36] or with chronic comorbidity. Several non-specific clinical features, such as fatigue, weakness, and decreased energy, as well as sexual impairment may be clinical manifestations. The EMAS study showed that a triad of sexual symptoms, including low libido, reduced spontaneous erections and ED, are typically associated with a decrease in serum testosterone levels [10]. Conversely, psychological and physical symptoms were less informative [10]. The mainstay of LOH diagnosis includes signs and symptoms consistent with hypogonadism, coupled with biochemical evidence of low morning serum total testosterone levels on two or more occasions, measured with a reliable assay. Testosterone levels show a circadian variation, which persist in ageing men [61, 62]. Likewise, testosterone levels are potentially influenced by food intake [63]; hence, serum total testosterone should be measured in fasting conditions and in the morning (between 07.00 and 11.00 hours). A confirmatory measurement should always be undertaken in the case of a primary pathological value, and certainly before starting any testosterone therapy. Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) represents the gold standard and most accurate method for sex steroid evaluation; however, standardised automated platform immuno-assays for total testosterone assessment demonstrate a good correlation with LC-MS/MS [64]. Conversely, available immuno-assays are not able to provide an accurate estimation of fT; therefore, direct fT evaluation with these methods is not recommended and should be avoided [41]. Liquid chromatography-tandem mass spectrometry remains the standard method for fT determination. Alternatively, fT can be derived from specific mathematical calculations taking into account serum SHBG and albumin levels [65] (http://www.issam.ch/freetesto.htm). Data from available meta-analyses have documented that testosterone therapy is ineffective when baseline levels are > 12 nmol/L (3.5 ng/mL). Positive outcomes are documented when testosterone levels are < 12 nmol/L, being higher in symptomatic patients with more severe forms of hypogonadism (< 8 nmol/L). Hence, 12 nmol/L should be considered as a possible threshold for starting testosterone therapy in the presence of hypogonadal symptoms [21, 66]. As reported above, clinical conditions that may interfere with SHBG levels, evaluation of fT should be considered to better estimate actual androgen levels (Figure 2). Unfortunately, despite its potential clinical value [67], no validated thresholds for fT are available from clinical studies and this represents an area of uncertainty; however, some data indicate that fT levels < 225 pmol/L (6.5 ng/dL) are associated with hypogonadal symptoms [10, 51, 68, 69]. The determination of LH must be performed along with prolactin (PRL) when pathological total testosterone levels are detected, in order to correctly define the underlying conditions and exclude possible organic causes (Figure 2). Due to its negative influence on libido, PRL can also be considered as first-line screening in patients with reduced sexual desire. In addition, pituitary magnetic resonance imaging (MRI) scanning, as well as other pituitary hormone evaluations, is required in the presence of specific symptoms such as visual disturbances, headache [70, 71] or when hyperprolactinemia is confirmed. Limited evidence suggests performing pituitary MRI also in the case of severe hypogonadism (< 6 nmol/L, 1.75 ng/mL) with inadequate gonadotropin levels (Figure 2) [70, 71].

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Figure 2: Diagnostic evaluation of Late-Onset Hypogonadism Check symptoms and signs suggesve for hypogonadism Check for drugs and substances that can interfere with T producon/acon Check for concomitant metabolic diseases: obesity/metabolic syndrome/diabetes Check for potenal testosterone therapy contraindicaons Measure fasng and morning (7-11 am) total T (consider PRL measurement if low desire or other suggesve symptoms are present) (consider SHBG and free-T calculaon when indicated) (consider LH when T deficiency pathophysiology must be invesgated)

TT < 12 nM hypogonadism possible

TT > 12 nM/ reduced cFT hypogonadism possible

TT > 12 nM hypogonadism unlikely

Repeat TT measurements along with LH PRL +/-SHBG cFT

TT < 12 nM (reduced cFT) and LH reduced/ inappropriate normal

TT < 12 nM (reduced cFT) and LH elevated

Secondary hypogonadism

Check for drugs and substances that can interfere with T producon/acon. Check for concomitant metabolic disease: obesity/ metabolic syndrome/diabetes

Primary hypogonadism

TT < 8 nM

TT < 6nM/ elevated PRL Headache/visual disturbances

Perform pituitary MRI

Possible specific therapy Invesgate if drugs or substances that may interfere with hypothalamic-pituitary axis can be eliminated. Suggest modifying potenal interfering condions obesity /underweight or other metabolic disturbances

Rule out testosterone therapy possible contraindicaons

Ferlity desired

Gonadotropin therapy

Testosterone therapy trial

TT = total testosterone; cFT = calculated free testosterone; PRL = prolactin; SHBG = sex hormone-binding globulin; LH = luteinising hormone; MRI = Magnetic resonance imaging.

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3.5.2 History taking Specific symptoms associated with LOH are shown in Table 3. History of surgical intervention for cryptorchidism or hypospadias must be taken into account as possible signs of congenital defects. Likewise, chronic and systemic comorbidity must be comprehensively investigated in every patient. Use of drugs that potentially interfere with the HPG axis should be ruled out (Table 2). Acute diseases are associated with development of functional hypogonadism and determination of serum total testosterone levels should be avoided in these conditions. However, recent data derived from SARS-CoV-2 infected patients showing worse outcomes in hypogonadal subjects suggest that the role of testosterone in the case of acute illness should be clarified [72, 73]. Several self-reported questionnaires or structural interviews have been developed for screening of hypogonadism. Although these case-history tools have demonstrated clinical utility in supporting the biochemical diagnosis of hypogonadism, or in the assessment of testosterone therapy outcomes, their specificity remains poor and they should not be used for a systematic screening of hypogonadal men [74]. Table 3: Specific symptoms associated with LOH

More specific

Less specific

Sexual symptoms - Reduced libido - Erectile dysfunction - Decreased spontaneous/ morning erections - Reduced frequency of sexual intercourse - Reduced frequency of masturbation - Delayed ejaculation

Physical symptoms - Decreased vigorous activity - Difficulty walking >1 km - Decreased bending

Psychological symptoms - Low mood/mood deflection - Decreased motivation - Fatigue

- Hot flushes - Decreased energy -D  ecreased physical strength/function/activity

- Concentration or mnemonic difficulties - Sleep disturbances

3.5.3 Physical examination Since obesity is frequently associated with hypogonadism (mostly functional), the determination of body mass index (BMI) and the measurement of waist circumference are strongly recommended in all individuals. Testicular and penile size, as well the presence of sexual secondary characteristics can provide useful information regarding overall androgen status. In addition, upper segment/lower segment ratio (n.v. > 0.92) and arm-span to height ratio (n.v. < 1.0) can be useful to identify a eunochoid body shape, especially in subjects with pre-pubertal hypogonadism or delayed puberty. Finally, digital rectal examination (DRE) should be performed in all subjects to exclude prostate abnormalities before testosterone therapy (any type) or to support suspicion of hypogonadism [75]. 3.5.4

Summary of evidence and recommendations for the diagnostic evaluation of LOH

Summary of evidence Sexual symptoms are the most specific symptoms associated with LOH. Diagnosis of LOH should be based on specific signs and symptoms of androgen deficiency, together with consistently low serum testosterone levels. Functional hypogonadism is a consequence of comorbidity/concomitant drugs, which can impair testosterone production in adulthood. The diagnosis of functional hypogonadism is a diagnosis of exclusion, after ruling out organic causes of hypogonadism.

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Recommendations Check for concomitant diseases, drugs and substances that can interfere with testosterone production/action. Total testosterone must be measured in the morning (07.00 and 11.00 hours) and in the fasting state, with a reliable method. Repeat total testosterone on at least two separate occasions when < 12 nmol/L and before starting testosterone therapy. 12 nmol/L total testosterone (3.5 ng/mL) represents a reliable threshold to diagnose late onset hypogonadism (LOH). Consider sex hormone-binding globulin and free-testosterone calculation when indicated. Calculated free-testosterone < 225 pmol/L has been suggested as a possible cut-off to diagnose LOH. Analyse luteinising hormone (LH) and follicle-stimulating hormone (FSH) serum levels to differentiate between primary and secondary hypogonadism. Consider prolactin (PRL) measurement if low sexual desire (or other suggestive signs/ symptoms) and low or low-normal testosterone is present. Perform pituitary magnetic resonance imaging (MRI) in secondary hypogonadism, with elevated PRL or specific symptoms of a pituitary mass and/or presence of other anterior pituitary hormone deficiencies. Perform pituitary MRI in secondary severe hypogonadism (total testosterone < 6 nmol/L).

3.5.5

Strong Strong Strong Strong Weak Strong Strong Strong

Weak

Recommendations for screening men with LOH

Recommendations Screen for late onset hypogonadism (LOH) (including in T2DM) only in symptomatic men. Do not use structured interviews and self-reported questionnaires for systematic screening for LOH as they have low specificity.

3.6

Strength rating Strong

Strength rating Strong Strong

Treatment of LOH

3.6.1 Indications and contraindications for treatment of LOH Patients with symptomatic hypogonadism (total testosterone < 12 nmol/L) without specific contraindications are suitable candidates to receive testosterone therapy (Table 4). Absolute contraindications are untreated breast cancer and prostate cancer (PCa). Acute cardiovascular events as well as uncontrolled or poorly controlled congestive heart failure and severe lower urinary tract symptoms (LUTS) [International Prostate Symptom Score (IPSS) score > 19] represent other contraindications, as there is insufficient information on the long-term effects of testosterone therapy in these patients [66]. A positive family history for venous thromboembolism requires further analysis to exclude a condition of undiagnosed thrombophilia-hypofibrinolysis [76]. These patients need to be carefully counselled prior to testosterone therapy initiation. A haematocrit (HCT) > 54% should require testosterone therapy withdrawal, reduction in dose, change of formulation and venesection depending on the clinical situation to avoid any potential cardiovascular complications. Lower baseline HTC (48-50%) should be carefully evaluated before testosterone therapy initiation, to avoid pathological increases during treatment, especially in high-risk men such as those with chronic obstructive pulmonary disease (COPD) or Obstructive Sleep Apnoea Syndrome (OSAS). Accordingly, the Framingham Heart Study showed that HCT > 48% represented a condition associated with increased risk of coronary artery disease (CAD) and mortality and was associated with cardiovascular disorders [77]. Finally, testosterone therapy suppresses gonadotropin and endogenous testosterone secretion as well as spermatogenesis. Hence, testosterone therapy is contraindicated in individuals who desire fertility [78]. Secondary hypogonadism is characterised by low or inappropriately normal gonadotropin levels; therefore, the rationale is to substitute the gonadotropin deficiency with FSH and LH analogues, if fertility is desired [79]. Table 4: Main contraindications of testosterone therapy

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Absolute contraindications

Relative contraindication

Locally advanced or metastatic prostate cancer (PCa) Male breast cancer Men with an active desire to have children Haematocrit ≥ 54% Uncontrolled or poorly controlled congestive heart failure IPSS score > 19 Baseline haematocrit 48-50% Familial history of venous thromboembolism

3.6.2 Testosterone therapy outcomes 3.6.2.1 Sexual dysfunction Sexual concerns are the main symptoms of hypogonadal patient [5, 10, 80, 81]. A consistent body of evidence shows that testosterone therapy in hypogonadal men (total testosterone < 12 nmol/L) may have a beneficial effect on several aspects of sexual life; in contrast, there is no evidence of benefits in using testosterone therapy for treating sexual dysfunction in eugonadal men [53, 66, 82, 83]. The beneficial effect on sexual function seems to be more related to testosterone level normalisation than the specific testosterone formulations used [83, 84]. A recent meta-analysis of only placebo-controlled RCTs using the International Index of Erectile Function (IIEF) [85] as a possible tool for outcome evaluation, showed that testosterone therapy significantly improves erectile function (as measured by IIEF-Erectile Function domain score) and that patients with more severe hypogonadism (i.e., total testosterone < 8 nmol/L) are more likely to achieve better improvement than patients with milder hypogonadism (i.e., total testosterone < 12 nmol/L). Similar results were observed for sexual desire; however, the presence of metabolic comorbidity (such as diabetes and obesity) decreased the magnitude of these improvements. In particular, testosterone therapy alone resulted in a clinically effective outcome only in patients with milder ED [66]. Other sexual function parameters, such as intercourse, orgasm and overall satisfaction, were all improved compared with placebo [66]. Men with comorbidity such as diabetes usually show modest improvements in terms of sexual function after testosterone therapy and may potentially require concomitant phosphodiesterase type 5 inhibitors (PDE5Is) to improve effectiveness [5, 83]. However, the specific beneficial effect derived from the combined use of testosterone therapy and PDE5Is is not completely clear [53]. Similarly, information related to the combined use of testosterone therapy with other ED drug therapies is lacking [5, 83]. The Sexual Function Trial of the Testosterone Trials (TTrials) (one of the largest placebo-controlled trials on testosterone therapy) documented consistent improvements in 10 of 12 measures of sexual activities in older (≥ 65 years) hypogonadal men, particularly in frequency of intercourse, masturbation and nocturnal erections (as measured by PDQ-Q4) [86]. The magnitude in improvement was shown to be proportional to the increase in serum total testosterone, fT and oestradiol levels, it was not possible to demonstrate a threshold level [87]. A study of 220 men with MetS with or without T2DM also found that sexual function improved in men who reported sexual problems with improvement in IIEF scores with specific increases in libido and sexual satisfaction [24]. 3.6.2.2 Body composition and metabolic profile Late onset hypogonadism is associated with a greater percentage fat mass and a lesser lean mass compared to testosterone-replete men [88]. The major effect of low testosterone is to increase visceral adiposity but also leads to deposition of lipids in the liver and muscle and is associated with atherosclerosis [19]. Some published data have suggested that testosterone therapy reduces percentage body fat and increases lean mass [89]. Testosterone therapy has also been found to decrease waist circumference, body weight and BMI, with these effects more predominant after 12 months of treatment [89-91]. However, it should be recognised that these results are mainly derived from registry and observational trials, which have important limitations due to the risk of selection bias for the non-random assignment of testosterone exposure. Accordingly, data derived from RCTs showed only an improvement of fat mass and lean mass of the same amount without any modifications in body weight [21]. 3.6.2.3 Mood and cognition Several observational studies have documented a relationship between depressive symptoms, reduced QoL and hypogonadism [92, 93]. However, the specific relationship between hypogonadism and the incidence of depression is still unclear [93]. Only a few placebo-controlled RCTs have investigated the role of testosterone

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therapy in improving depressive symptoms. Data derived from TTrials showed that testosterone therapy improved mood, and depressive symptoms as continuous measures using several instruments [86]. However, the final effect was small in magnitude. In line with these data, the largest meta-analysis of available studies, including 1,890 hypogonadal men (baseline total testosterone < 12 nmol/L or fT < 225 pmol/L) men from 27 RCTs, documented that the positive effect of testosterone therapy was particularly evident in patients with milder symptoms [94]. The BLAST study of testosterone therapy in T2DM reported that those men with depression were less likely to respond with regard to symptoms of sexual dysfunction compared to men without depression [29]. Robust data on the effect of testosterone therapy on QoL are limited. Although recent metaanalyses suggest a significant effect of testosterone therapy over placebo, the magnitude is low and the heterogeneity high, therefore reducing the scientific value of the effect [84, 95]. The role of testosterone therapy in patients with cognitive impairment is even more uncertain. The TTrials evaluated the effect of testosterone therapy in 493 individuals with age-associated memory impairment in order to assess possible improvement of several aspects of cognitive function. However, the final results failed to demonstrate any beneficial effect of testosterone therapy in improving cognitive function [86]. 3.6.2.4 Bone Evidence suggests that bone mineralisation requires circulating sex steroids within the normal range [96]. The possible association between mild hypogonadism and osteopenia/osteoporosis is weak, whereas severe hypogonadism (total testosterone < 3.5 nM) is frequently associated with bone loss and osteoporosis, independent of patient age [96]. Two independent meta-analyses showed a positive effect of testosterone therapy on bone mineral density (BMD), with the highest effect at the lumber level [97, 98]. Similarly, data derived from TTrials confirmed that testosterone therapy increased BMD in hypogonadal ageing men, particularly at the lumbar level [86]. However, available data are insufficient to determine the effect of testosterone therapy alone on the risk of fractures [96]. The use of testosterone therapy as an adjunct to anti-resorptive treatment in hypogonadal patients at high risk of fractures has not been established. Therefore, anti-resorptive therapy must be the first-choice treatment in hypogonadal men at high risk for bone fractures. The combination of anti-resorptive treatment and testosterone therapy should be offered only in conjunction with hypogonadism-related symptoms. 3.6.2.5 Vitality and physical strength The role of testosterone in stimulating muscle growth and strength is well established. Accordingly, androgenicanabolic steroids (AAS) have been used as performance-enhancing agents to increase physical performance in competitive sport [99]. In this regard, testosterone therapy in hypogonadal men has been shown to increase muscle mass and reduce fat mass, with limited effects on final weight [21]. Despite this evidence, the role of testosterone therapy in older men with mobility limitations remains unclear. The National Health and Nutrition Examination Survey 1999-2004 [100] was unable to detect any association between overall circulating testosterone levels and the amount of physical activity. However, among non-obese men, those in the highest physical activity tertile were significantly less likely to have low or low-normal testosterone than those in the lowest tertile. Data from TTrials indicated that testosterone therapy did not substantially increase the fraction of men whose 6-minute walking distance increased > 50 m or the absolute increase in the distance walked by those enrolled in the physical function trial [86]. However, when the whole population of the TTrials was considered, a significant, although modest, positive effect on these two parameters was reported [86]. Similar data were derived from the Vitality Trial [86]. 3.6.2.6

Summary of evidence and recommendations for testosterone therapy outcome

Summary of evidence Testosterone therapy can improve milder forms of ED and libido in hypogonadal men. Testosterone therapy can improve other sexual symptoms, including intercourse frequency, orgasm and overall satisfaction. Testosterone therapy can similarly increase lean mass, reduce fat mass, and improves insulin resistance. Testosterone therapy can improve weight, waist circumference and lipid profile, but findings are not unique. Testosterone therapy can improve milder depressive symptoms in hypogonadal men. Testosterone therapy can improve bone mineral density, but information related to fracture risk is lacking.

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Recommendations The use of testosterone therapy in eugonadal men is not indicated. Use testosterone therapy as first-line treatment in patients with symptomatic hypogonadism and mild erectile dysfunction (ED). Use combination of phosphodiesterase type 5 inhibitors and testosterone therapy in more severe forms of ED as it may result in better outcomes. Use conventional medical therapies for severe depressive symptoms and osteoporosis. Do not use testosterone therapy to improve body composition, reduce weight and benefit cardio-metabolic profile. Do not use testosterone therapy to improve cognition vitality and physical strength in ageing men.

Strength rating Strong Strong Weak Strong Weak Strong

3.6.3 Choice of treatment 3.6.3.1 Lifestyle factors As reported above, functional hypogonadism is frequently associated with obesity and metabolic disorders [101]. Therefore, weight loss and lifestyle changes should be the first approach for all overweight and obese men with hypogonadism. A previous meta-analysis documented that a low-calorie diet is able to revert obesity-associated secondary hypogonadism by increasing total testosterone and fT, reducing oestrogens and restoring normal gonadotropin circulating levels [102]. This was confirmed in a recent updated meta-analysis showing that the increase in testosterone is significantly associated with weight reduction [103]. Similar results can be obtained through physical activity, which is associated with the duration of scheduled exercise and weight loss obtained [103]. However, it should be recognised that the increase in testosterone levels observed after a low- calorie diet and physical activity is small (1-2 nmol) [102, 103]. It should also be recognised that 60-86% of weight lost is regained after 3 years and 75-121% after 5 years [104]. A greater testosterone increase can be achieved through bariatric surgery, which results in an average increase of about 10 nmol/L depending on the degree of weight loss [103]. Lifestyle changes represent an essential part of the management of obesity; however, some evidence suggests that when compared to lifestyle modifications alone, testosterone therapy-treated obese men benefit most from relief of their symptoms associated with testosterone deficiency, whereas those not treated did not benefit [79]. There is limited evidence to suggest that combination of lifestyle interventions and testosterone therapy in symptomatic hypogonadal men might result in better outcomes [88]. There is a large, on-going placebo-controlled RCT that aims to determine whether lifestyle intervention alone or in combination with testosterone therapy reduces T2DM incidence and improves glucose tolerance [105]. 3.6.3.2 Medical preparations Several testosterone formulations are available (Table 5). Direct comparisons among different testosterone products are still lacking. Candidates for testosterone therapy should be adequately informed about the possible risks and benefits of all available testosterone preparations. The final choice should be based on the clinical situation, testosterone formulation availability, and patient needs and expectations [106]. 3.6.3.2.1 Oral formulations The esterification of testosterone with a long-chain fatty acid (testosterone undecanoate; TU) enables testosterone to be absorbed by the intestine through the lymphatic system, by-passing liver metabolism. This formulation has been available in oleic acid since the 1970s, and it has been recently reformulated in a mixture of castor oil and propylene glycol laureate (TU caps), to allow the drug to be maintained at room temperature without degradation [107]. The main limitation is related to the poor bioavailability, which is strongly dependent on dietary fat content [107]. Recently, the US Food and Drug Administration (FDA) approved a new formulation of oral TU incorporating a liquid-filled hard capsule drug delivery system and a higher amount (225 mg) of the compound, which improves oral availability (https://www.fda.gov/media/110187/download). In an open label study of approximately 4 months’ duration (NCT02722278), 145 (87%) of 166 hypogonadal men enrolled who received the TU caps formulation had mean total testosterone concentration within the normal eugonadal range at the end of treatment (https://www.fda.gov/media/110187/download). However, the TU caps compound is not available in Europe. Mesterolone is a 5α-DHT derivate available for oral administration. Along with DHT, mesterolone cannot be converted to oestrogens and can only be used for a limited period and specific indications, such as the presence of painful gynaecomastia. However, the lack of a full spectrum of testosterone bioactivity strongly limits its long-term use [107].

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3.6.3.2.2 Parenteral formulations Injectable testosterone preparations can be classified according to their half-lives (Table 5). Testosterone propionate is a short-term ester formulation requiring multiple fractionated doses (usually 50 mg, every 2-3 days), thus representing a major limitation for its use [107]. Cypionate and enanthate-T esters are short-term formulations, requiring administration every 2-4 weeks. A formulation containing mixed testosterone esters (TU, isocaproate, phenyl propionate, propionate - Sustanon®) which allows some benefit of a smoother release of testosterone into the circulation is available in some countries. The use of these older formulations is associated with wide fluctuations in plasma testosterone concentrations and is often reported as unpleasant by patients and potentially resulting in adverse effects, such as polycythaemia [107, 108]. A longer-lasting TU injectable formulation is widely available [107]; which has a good safety/benefit profile allowing the maintenance of normal stable testosterone levels at a dose of 1,000 mg initially every 12 weeks, following a 6-week loading dose, but can be adjusted to a frequency of 10-14 weeks dependent on the trough (pre-injection level) after 3-5 injections to maintain levels in the therapeutic range (usually > 12 and < 18 nmol/L) [107, 109]. 3.6.3.2.3 Transdermal testosterone preparations Among the available transdermal formulations, testosterone gels represent the most frequently used preparations. The gel is quickly absorbed by the stratum corneum, creating a reservoir within the subcutaneous tissues from where testosterone is continuously delivered for 24 hours, after a single daily application. These formulations have been shown to normalise serum testosterone levels with an excellent safety profile [107]. The introduction of specific devices and skin enhancers has resulted in better skin penetration of the drugs, thus reducing potential adverse effects. Local skin adverse effects are limited when compared to those with traditional testosterone patches, but they potentially allow transference of testosterone during close contact with the skin surface. The risk can be reduced by wearing clothing or by applying the gel on skin surfaces not usually touched (e.g., the inner thigh surface) [107]. To reduce the total amount of gel applied and residual quantities remaining on the skin, new formulations of testosterone gel have been introduced with a testosterone concentration of 1.62-2% [107]. Another transdermal testosterone formulation includes a topical, alcohol-based testosterone (2%) solution, which must be applied to the underarm once daily, using a metered dose applicator [107]. This testosterone formulation is not available in Europe. Testosterone levels should be monitored to optimise the testosterone dose. Blood collection is best taken at 2-4 hours after gel application to use the peak level of testosterone absorbed as a reference for adequate therapeutic levels. Levels of testosterone after application can vary and a repeat measurement may be indicated especially as sometimes, inadvertently, the skin over the vene-puncture site can be contaminated by the gel, leading to falsely elevated results. In some European countries, DHT is available as a hydroalcoholic 2.5% gel. It is rapidly absorbed, reaching a steady state in 2-3 days. Similar to that reported for mesterolone, DHT is not aromatised but can be useful for treating particular conditions, such as gynaecomastia and microphallus [107]. 3.6.3.2.4 Transmucosal formulations 3.6.3.2.4.1 Transbuccal Testosterone preparations A testosterone buccal system is still available in several countries. It consists on a sustained-release mucoadhesive buccal-testosterone-tablet requiring twice-daily application to the upper gums. The tablet does not dissolve completely in the mouth and must be removed after 12 hours. This formulation has been proven to restore testosterone levels within the physiological range with minimal or transient local problems, including gum oedema, blistering and gingivitis [107]. 3.6.3.2.4.2 Transnasal testosterone preparations A gel for intranasal administration is available in some countries, including the USA and Canada. It requires administration two or three times daily using a specific metered-dose pump. The application is rapid, noninvasive, convenient, and avoids secondary transference observed with other topical products [107]. 3.6.3.2.5 Subdermal depots The implantation of testosterone pellets, available in the USA, UK and Australia, represents the longest available testosterone formulation lasting from 4-7 months. However, the procedure is invasive and may be unattractive to patients [107]. 3.6.3.2.6 Anti-oestrogens Anti-oestrogens, including selective oestrogen receptor (ER) modulators (SERMs) and aromatase inhibitors (AI) have been suggested as off-label treatments to restore testosterone levels and fertility in men with functional secondary hypogonadism or idiopathic infertility. They work by preventing down-regulation of the HPG axis by oestrogens and, for this reason are particularly useful in men with obesity and metabolic disorders [103]. In

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25

the latter case, the hypothesis is that the excess of adipose tissue leads to increased aromatase activity and oestrogens levels resulting in impairment of the HPG [101]. Due to their putative mechanism of action, they require an intact HPG axis and cannot work in primary hypogonadism or secondary hypogonadism due to organic damage of the HPG axis. Both types of SERMs, which bind ERs with an agonist or antagonist effect depending upon the target tissue, and AIs, which prevent androgens from being converted into oestrogens by aromatase, have been used in clinical practice [107]. The evidence published so far is poor; all these products are off-label treatments and SERMs, due to their agonistic effect on venous vessels, could predispose men to the development of venous thromboembolism [107]. In this context patients should be warned of the potential increased risk of venous thromboembolism, although data are lacking. Long-term use of these agents can lead to reduced bone density and development of osteoporosis, potentially increasing fracture risk. 3.6.3.2.7 Gonadotropins Considering the aforementioned limitations regarding the use of anti-oestrogens, gonadotropin therapy should be considered the standard in men with secondary hypogonadism who desire paternity (Table 5) [107]. The treatment is based on the use of human chorionic gonadotropin (hCG), purified from the urine of pregnant women. The most expensive recombinant hCG (rhCG) and LH (rLH) formulations do not offer clinical advantages [107]. According to a meta-analysis of the available evidence, hCG should be administered with FSH as combined therapy results in better outcomes. Similar to recombinant hCG, recombinant FSH (rFSH) does not seem to offer any advantages compared to urinary-derived preparations [110]. More details on the use of gonadotropins are provided in Section 10. Table 5: Available preparations for hypogonadism treatment Formulation

Chemical structure t 1/2

GONADOTROPINS Human chorionic gonadotrophin (HCG) Extractive HCG purified from the urine of pregnant women Recombinant Human recombinant HCG Luteotropic hormone (LH) Recombinant Human recombinant LH Follicle-stimulating hormone (FSH) Extractive FSH purified from urine of pregnant women Recombinant Human recombinant FSH TESTOSTERONE PREPARATIONS Oral Testosterone 17-α-hydroxylester undecanoate

Mesterolone

26

1α-methyl-4, 5α-dihydrotestosterone

NA

NA

Standard dosage

Advantages

1,000-2,000 Low cost IU 3 times/week No data in NA men

Disadvantages

Multiple weekly administration

NA

No data in men

NA

NA

75-150 IU Low cost 3 times/week

Multiple weekly administration

NA

75-150 IU 3 times/week

Multiple weekly administration

4 hours

120-240 mg 2-3 times daily

- Reduction of liver involvement - Oral convenience - Modifiable dosage

12 hours

50-100 mg 2-3 times daily

- Oral convenience - Modifiable dosage - Useful in gynaecomastia

- Unpredictable absorption depending on dietary fat content - Must be taken with meals - Not aromatisable

SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021

Parental Testosterone enanthate

17-α-hydroxylester

Testosterone cypionathe

17-α-hydroxylester

Testosterone propionate

17-α-hydroxylester

Testosterone ester mixture Propionate (30mg) Phenylpropionate (60 mg) Isocaproate (60 mg) Decanoate (100 mg) Testosterone undecanoate in castor oil

4-androsten-3-one17 beta-hydroxyandrost-4-en-3-one

4-5 days

250 mg every - Low cost 2-3 weeks -S  hort-acting preparation allowing drug withdrawal in case of adverse effects 8 days 200 mg every - Low cost 2-3 weeks - Short-acting preparation allowing drug withdrawal in case of adverse effects 20 100 mg every - Low cost hours 2 days - Very short-acting preparation allowing drug withdrawal in case of adverse effects 4-5 250 mg every - Low cost days 3 weeks - Short-acting preparation allowing drug withdrawal in case of adverse effects

34 days

1,000 mg every 10-14 weeks *750 mg every 10 weeks

- Steady-state testosterone level without fluctuation - Long-lasting - Less frequent administration

Surgical implants Native testosterone

--

4-6 200 mg implants lasting up to 6 months

- Long duration and constant serum testosterone level

TRANSDERMAL Testosterone Native testosterone patches

10 hours

50-100 mg/ day

Testosterone gel 1-2%

Native testosterone

6 hours

50-100 mg/ day

Steady-state testosterone level without fluctuation Steady-state testosterone level without fluctuation

Underarm testosterone (testosterone solution 2%)

Native testosterone

NA

60-120 mg/ day

Dihydrotestosterone gel 2.5%

Native dihydrotestosterone

NA

34-70 mg/day - Steady-state testosterone level without fluctuation - Useful in gynaecomastia

17-α-hydroxylester

SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021

Steady-state testosterone level without fluctuation

- Fluctuations in circulating testosterone levels - Multiple injections - Relative risk of polycythemia - Fluctuations in circulating testosterone levels - Multiple injections - Relative risk of polycythemia - Fluctuations in circulating testosterone levels - Multiple injections - Relative risk of polycythemia - Fluctuations in circulating testosterone levels - Multiple injections - Relative risk of polycythemia

- Pain at injection site - Long-acting preparation not allowing rapid drug withdrawal in case of adverse effects - Placement is invasive - Risk of extrusion and site infections - Skin irritation - Daily administration - Possible transfer during intimate contact - Daily administration - Possible transfer during intimate contact - Daily administration - Possible transfer during intimate contact - Daily administration - Not aromatisable

27

TRANSMUCOSAL Testosterone Native testosterone buccal system

12 hours

60 mg 3 times daily

Steady-state testosterone level without fluctuation

Testosterone nasal

6 hours

33 mg 3 times daily

Steady-state testosterone level without fluctuation

Native testosterone

- Possible oral irritation - Twice-daily dosing - Unpleasant taste - Nasal irritation - Multiple daily administration

NA = not applicable. 3.6.3.3

Summary of evidence and recommendations for choice of treatment for LOH

Summary of evidence Weight loss obtained through a low-calorie diet and regular physical activity result in a small improvement in testosterone levels. Testosterone gels and long-acting injectable TU represent T preparations with the best safety profile. Gonadotropins treatment can be used to restore fertility in men with secondary hypogonadism.

Recommendations Treat, when indicated, organic causes of hypogonadism (e.g., pituitary masses, hyperprolactinemia, etc). Improve lifestyle and reduce weight (e.g., obesity); withdraw, when possible, concomitant drugs that can impair testosterone production; treat co-morbidity before starting testosterone therapy. Fully inform patients about expected benefits and adverse effects of any treatment option. Select the testosterone preparation in a joint decision process, only with fully informed patients. The aim of testosterone therapy is to restore serum testosterone concentration to the average normal range for young men. Use testosterone gels rather than long-acting depot administration when starting initial treatment, so that therapy can be adjusted or stopped in the case of treatment-related adverse effects.

3.7

Strength rating Strong Weak

Strong

Weak Weak

Safety and follow-up in hypogonadism management

3.7.1 Hypogonadism and fertility issues The aim of pharmacological management of hypogonadism is to increase testosterone levels. The first choice is to administer exogenous testosterone. However, while exogenous testosterone has a beneficial effect on the clinical symptoms of hypogonadism, it also inhibits gonadotropin secretion by the pituitary gland, resulting in impaired spermatogenesis and sperm cell maturation [111]. Therefore testosterone therapy is contraindicated in hypogonadal men seeking fertility treatment [78]. When secondary hypogonadism is present, gonadotropin therapy can maintain normal testosterone levels and restore sperm production [5]. 3.7.2 Male breast cancer In vitro and in vivo studies have clearly documented that breast cancer growth is significantly influenced by testosterone and/or by its conversion to E2 through different mechanisms and pathways [112]. Accordingly, the use of SERMs still represents an important therapeutic option in the management of this cancer [112]. No information is available on the role of testosterone therapy in patients successfully treated for male breast cancer; therefore, treated and active male breast cancer should be recognised as absolute contraindications for testosterone therapy. 3.7.3 Lower urinary tract symptoms/benign prostatic hyperplasia Based on the assumption that prostate growth is dependent on the presence of androgens, historically testosterone therapy historically has raised some concerns regarding the possibility of aggravating LUTS in patients affected by benign prostatic hyperplasia (BPH) associated with prostate enlargement [75, 113]. However, pre-clinical and clinical data have indicated that low rather than high androgen levels may decrease bladder capacity, alter tissue histology and decrease the ratio of smooth muscle to connective tissue, thus impairing urinary dynamics [75, 113].

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A trial of 60 patients undergoing testosterone therapy for 6 months showed no significant differences in post-voidal residual urine and prostate volume, while storage symptoms as measured by IPSS significantly improved, despite an increase in prostate-specific antigen (PSA) level. A larger pre-treatment prostate volume was a predictive factor of improvement in LUTS [114]. A long-term study of 428 men undergoing testosterone therapy for 8 years demonstrated significant improvements in IPSS, no changes max flow rate (Qmax) and residual urine volume, but also a significant increase in prostate volume [115]. Similar data from the Registry of Hypogonadism in Men (RHYME), including 999 patients with a follow-up of 3 years, did not document any difference in PSA levels or total IPSS in men undergoing testosterone therapy, compared to untreated patients [116]. Similar results were reported in an Italian registry (SIAMO-NOI), collecting data from 432 hypogonadal men from 15 centres [117]. Meta-analyses have not found significant changes in LUTS between patients treated with testosterone or placebo [118-124]. According to the most recent literature, there are no grounds to discourage testosterone therapy in hypogonadal patients with BPH/LUTS and there is evidence of limited benefit from androgen administration. The only concern is related to patients with severe LUTS (IPSS > 19), as they are usually excluded from RCTs, therefore limiting the long-term safety data of testosterone therapy in this specific setting [75]. 3.7.4 Prostate cancer (PCa) A considerable number of observational studies have failed to demonstrate any association between circulating higher testosterone levels and PCa [125]. In contrast, studies investigating the relationship between low levels of testosterone and risk of PCa have found that men with very low levels of fT have a reduced risk of developing low-to-intermediate-grade PCa, but have a non-significantly increased chance of developing highgrade PCa [125]. This peculiar pattern was also reported in trials such as the Health Professionals Follow-up Study, the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE), with varying magnitudes of significance [126]. The most recent meta-analysis, including 27 placebo-controlled, RCTs, found no evidence of increased PSA levels following testosterone therapy for one year. When considering 11 studies reporting on the occurrence of PCa, the meta-analysis found no evidence of increased risk of PCa. However, a 1-year follow-up may be considered too short to draw conclusions on PCa occurrence. Furthermore, the analysis was restricted to studies with > 1-year follow-up, but no significant changes in PSA levels nor increased risk of PCa were found [119]. After 5-years’ median follow-up in three independent registry studies with > 1,000 patients undergoing testosterone therapy, PCa occurrence remained at all times below the reported incidence rate in the general population [127]. Similar results were reported by a more recent large observational study including 10,311 men treated with testosterone therapy and 28,029 controls with a median follow-up of 5.3 years [128]. The same study, also showed that the risk of PCa was decreased for men in the highest tertile of testosterone therapy cumulative dose exposure as compared with controls [128]. With regards to PCa survivors, safety in terms of the risk of recurrence and progression has not yet been established. Limited data are available in the literature, with most case series not providing sufficient data to draw definitive conclusions (e.g., insufficient follow-up, small samples, lack of control arms, heterogeneity in study population and treatment regimen, etc.) [129]. More recently, a meta-analysis derived from 13 studies including 608 patients, of whom 109 had a history of high-risk PCa, with follow-up of 1-189.3 months [130], suggested that testosterone therapy did not increase the risk of biochemical recurrence, but the available evidence is poor, limiting data interpretation [130]. Similar considerations can be derived from another, larger meta-analysis of 21 studies [131]. It is important to recognise that most of the studies analysed included lowrisk patients with Gleason score < 8 [130]. In conclusion, recent literature does not support an increased risk of PCa in hypogonadal men undergoing testosterone therapy. Although it is necessary to avoid testosterone administration in men with advanced PCa, insufficient long-term prospective data on the safety of androgen administration in PCa survivors [131], without recurrence should prompt caution in choosing to treat symptomatic hypogonadal men in this setting. Specifically, patients should be fully counselled that the long-term effects of testosterone therapy in this setting are still unknown and requires further investigation. If an occult PCa is not detected before initiation of testosterone therapy, treatment may unmask the cancer detected by an early rise in PSA over 6-9 months of therapy. Due to the lack of strong evidence-based data on safety, the possible use of testosterone therapy in symptomatic hypogonadal men previously treated for PCa should be adequately discussed with the patients and limited to low-risk individuals. 3.7.5 Cardiovascular Disease Evidence suggests that hypogonadal men have an increased risk of CVD [132, 133]. Whether or not LOH is a cause or a consequence of atherosclerosis has not been clearly determined. Late-onset hypogonadism is associated with CV risk factors, including central obesity, insulin resistance and hyperglycaemia, dyslipidaemia (elevated total cholesterol, LDL-cholesterol, triglycerides and low HDL-cholesterol), pro-thrombotic tendency

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and chronic inflammatory state [133]. Atherosclerosis is a chronic inflammatory disease, that releases proinflammatory cytokines into the circulation, which are known to suppress testosterone release from the HPG axis. Evidence from RCTs of testosterone therapy in men with MetS and/or T2DM demonstrates some benefit in CV risk, including reduced central adiposity, insulin resistance, total cholesterol and LDL-cholesterol and suppression of circulating cytokines [14, 23-25, 29, 133]. However, due to the equivocal nature of these studies, testosterone therapy cannot be recommended for indications outside the specific symptoms. Published data show that LOH is associated with an increase in all-cause and CVD-related mortality [12, 134137]. These studies are supported by a meta-analysis that concluded that hypogonadism is a risk factor for cardiovascular morbidity [123] and mortality [138]. Importantly, men with low testosterone when compared to eugonadal men with angiographically proven coronary disease have twice the risk of earlier death [133]. Longitudinal population studies have reported that men with testosterone in the upper quartile of the normal range have a reduced number of CV events compared to men with testosterone in the lower three quartiles [134]. Androgen deprivation therapy for PCa is linked to an increased risk of CVD and sudden death [139]. Conversely, two long-term epidemiological studies have reported reduced CV events in men with high normal serum testosterone levels [140, 141]. Erectile dysfunction is independently associated with CVD and may be the first clinical presentation in men with atherosclerosis. The knowledge that men with hypogonadism and/or ED may have underlying CVD should prompt individual assessment of their CV risk profile. Individual risk factors (e.g., lifestyle, diet, exercise, smoking, hypertension, diabetes and dyslipidaemia) should be assessed and treated in men with pre-existing CVD and in patients receiving androgen deprivation therapy. Cardiovascular risk reduction can be managed by primary care clinicians, but patients should be appropriately counselled by clinicians active in prescribing testosterone therapy [80]. If appropriate, they could be referred to cardiologists for risk stratification and treatment of co-morbidity. No RCTs have provided a clear answer on whether testosterone therapy affects CV outcomes. The TTrial (n=790) in older men [142], the TIMES2 (n=220) [24] and the BLAST studies in men with MetS and T2DM and the pre-frail and frail study in elderly men - all of 1-year duration - did not reveal any increase in Major Adverse Cardiovascular Events (MACE) [24, 27, 142, 143]. In this context, MACE is defined as the composite of CV death, non-fatal acute myocardial infarction, acute coronary syndromes, stroke and cardiac failure. Randomised controlled trials between 3 and 12 months in men with known heart disease treated with testosterone have not found an increase in MACE, but have reported improvement in cardiac ischaemia, angina and functional exercise capacity [144-146]. The European Medicines Agency has stated that ‘The Co-ordination Group for Mutual recognition and Decentralisation Procedures-Human (CMDh), a regulatory body representing EU Member States, has agreed by consensus that there is no consistent evidence of an increased risk of heart problems with testosterone in men who lack the hormone (a condition known as hypogonadism). However, the product information is to be updated in line with the most current available evidence on safety, and with warnings that the lack of testosterone should be confirmed by signs and symptoms and laboratory tests before treating men with these drugs [147]. As a whole, as for MACE, current available data from interventional studies suggest that there is no increased risk with up to 3 years of testosterone therapy [148-151]. The weight of the currently published evidence has reported that testosterone therapy in men with diagnosed hypogonadism has neutral or beneficial actions on MACE in patients with normalised testosterone levels. The findings could be considered sufficiently reliable for a 3-year course of testosterone therapy, after which no available study can exclude further or long-term CV events [152, 153]. 3.7.5.1 Cardiac Failure Testosterone treatment is contraindicated in men with severe chronic cardiac failure because fluid retention may lead to exacerbation of the condition. Some studies including one of 12 months’ duration have shown that men with moderate chronic cardiac failure may benefit from low doses of testosterone, which achieve mid-normal range testosterone levels [145, 154, 155]. If a decision is made to treat hypogonadism in men with chronic cardiac failure, it is essential that the patient is followed up carefully with clinical assessment and both testosterone and haematocrit measurements on a regular basis. An interesting observation is that untreated hypogonadism increased the re-admission and mortality rate in men with heart failure [156]. 3.7.6 Erythrocytosis An elevated haematocrit is the most common adverse effect of testosterone therapy. Stimulation of erythropoiesis is a normal biological action that enhances delivery of oxygen to testosterone-sensitive tissues

30

SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021

(e.g., striated, smooth and cardiac muscle). Any elevation above the normal range for haematocrit usually becomes evident between 3 and 12 months after testosterone therapy initiation. However, polycythaemia can also occur after any subsequent increase in testosterone dose, switching from topical to parenteral administration and, development of co-morbidity, which can be linked to an increase in haematocrit (e.g., respiratory or haematological diseases). There is no evidence that an increase of haematocrit up to and including 54% causes any adverse effects. If the haematocrit exceeds 54% there is a testosterone independent, but weak associated rise in CV events and mortality [77, 157-159]. Any relationship is complex as these studies were based on patients with any cause of secondary polycythaemia, which included smoking and respiratory diseases. There have been no specific studies in men with only testosterone-induced erythrocytosis. Three large studies have not shown any evidence that testosterone therapy is associated with an increased risk of venous thromboembolism [160, 161]. However, one study showed that an increased risk peaked at 6 months after initiation of testosterone therapy, then declined over the subsequent period [162]. No study reported whether there was monitoring of haematocrit, testosterone and/or E2 levels. High endogenous testosterone or E2 levels are not associated with a greater risk of venous thromboembolism [163]. In one study venous thromboembolism was reported in 42 cases and 40 of these had diagnosis of an underlying thrombophilia (including factor V Leiden deficiency, prothrombin mutations and homocysteinuria) [164]. In a RCT of testosterone therapy in men with chronic stable angina there were no adverse effects on coagulation, by assessment of tissue plasminogen activator or plasminogen activator inhibitor-1 enzyme activity or fibrinogen levels [165]. A meta-analysis of RCTs of testosterone therapy reported that venous thromboembolism was frequently related to underlying undiagnosed thrombophilia-hypofibrinolysis disorders [76]. With testosterone therapy an elevated haematocrit is more likely to occur if the baseline level is toward the upper limit of normal prior to initiation. Added risks for raised haematocrit on testosterone therapy include smoking or respiratory conditions at baseline. Higher haematocrit is more common with parenteral rather than topical formulations. In men with pre-existing CVD extra caution is advised with a definitive diagnosis of hypogonadism before initiating testosterone therapy and monitoring of testosterone as well as haematocrit during treatment. Elevated haematocrit in the absence of co-morbidity or acute CV or venous thromboembolism can be managed by a reduction in testosterone dose, change in formulation or if the elevated haematocrit is very high by venesection (500 mL), even repeated if necessary, with usually no need to stop the testosterone therapy. 3.7.7 Obstructive Sleep Apnoea There is also no evidence that testosterone therapy can result in onset or worsening of sleep apnoea. Combined therapy with Continuous Positive Airway Pressure (CPAP) and testosterone gel was more effective than CPAP alone in the treatment of obstructive sleep apnoea [166]. In one RCT, testosterone therapy in men with severe sleep apnoea reported a reduction in oxygen saturation index and nocturnal hypoxaemia after 7 weeks of therapy compared to placebo, but this change was not evident after 18 weeks’ treatment and there was no association with baseline testosterone levels [167]. 3.7.8 Follow up Testosterone therapy alleviates symptoms and signs of hypogonadism in men in a specific time-dependent manner. The TTrials clearly showed that testosterone therapy improved sexual symptoms as early as 3 months after initiation [86]. Similar results have been derived from meta-analyses [53, 76]. Hence, the first evaluation should be planned after 3 months of treatment. Further evaluation may be scheduled at 6 months or 12 months, according to patient characteristics, as well as results of biochemical testing (see below). Table 6 summarises the clinical and biochemical parameters that should be monitored during testosterone therapy. Trials were designed to maintain the serum testosterone concentration within the normal range for young men (280–873 ng/dL or 9.6-30 nmol/L) [86]. This approach resulted in a good benefit/risk ratio. A similar approach could be considered during follow-up. The correct timing for evaluation of testosterone levels varies according to the type of preparation used (Table 5). Testosterone is involved in the regulation of erythropoiesis [108] and prostate growth [75], hence evaluation of PSA and haematocrit should be mandatory before and during testosterone therapy. However, it is important to recognise that the risk of PCa in men aged < 40 years is low. Similarly, the mortality risk for PCa in men aged > 70 years is not been considered high enough to warrant monitoring in the general population [168]. Hence, any screening for PCa through determination of PSA and DRE in men aged < 40 or > 70 years during testosterone therapy should be discussed with the patients. Baseline and, at least, annually glyco-metabolic profile evaluation may be a reasonable

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consideration, particularly in the management of functional hypogonadism. Testosterone therapy may be beneficial for hypogonadal men with low or moderate fracture risk [96]; therefore, dual energy X-ray absorptiometry (DEXA) bone scan may also be considered at baseline and 18-24 months following testosterone therapy, particularly in patients with more severe hypogonadism [96]. Digital rectal examination may detect prostate abnormalities that can be present even in men with normal PSA values. Hence, DRE is mandatory in all men at baseline and during testosterone therapy. The decision to stop testosterone therapy or to perform prostate biopsy due to PSA increase or prostate abnormalities should be based on local PCa guidelines. There is a large consensus that any increase of haematocrit > 54% during testosterone therapy requires therapy withdrawal and phlebotomy to avoid potential adverse effects including venous-thromboembolism and CVD, especially in high-risk individuals. In patients with lower risk of relevant clinical sequelae, the situation can be alternatively managed by reducing testosterone dose and switching formulation along with venesection. A positive family history of venousthromboembolism should be carefully investigated and the patient counselled with regard to testosterone therapy to avoid/prevent thrombophilia-hypofibrinolysis [76]. Finally, caution should be exercised in men with pre-existing CVD or at higher risk of CVD. Table 6: Clinical and biochemical parameters to be checked during testosterone therapy Parameters Clinical Symptoms Body Mass Index Waist circumference Digital rectal examination Blood pressure Biochemistry PSA (ng/mL) Haematocrit (%) Testosterone Lipid and glycaemic profile Instrumental DEXA 3.7.9

Year 1 of treatment Baseline 3 months

6/12 months

After year 1 of treatment Annually 18-24 months

X

X

X

X

X X X

X X X

X X X

X X X

X X X X

X X X

X X X X

X X X X

X

X

Summary of evidence and recommendations on risk factors in testosterone treatment

Summary of evidence Testosterone therapy is contraindicated in men with secondary hypogonadism who desire fertility. Testosterone therapy is contraindicated in men with active prostate cancer or breast cancer. Testosterone therapy does not increase the risk of prostate cancer, but long-term prospective follow-up data are required to validate this statement. The effect of testosterone therapy in men with severe lower-urinary tract symptoms is limited, as these patients are usually excluded from RCTs. There is no substantive evidence that testosterone therapy, when replaced to normal levels, results in the development of major adverse cardiovascular events. There is no evidence of a relationship between testosterone therapy and mild, moderate or CPAP-treated severe sleep apnoea. Recommendations Fully counsel symptomatic hypogonadal men who have been surgically treated for localised prostate cancer (PCa) and who are currently without evidence of active disease considering testosterone therapy, emphasising the benefits and lack of sufficient safety data on longterm follow-up. Restrict treatment to patients with a low risk for recurrent PCa (i.e., pre-operative PSA < 10 ng/mL; Gleason score < 7 (International Society for Urological Pathology grade 1); cT1-2a)* and treatment should start after at least 1 year follow-up with PSA level < 0.01 ng/mL. Safety data on the use of testosterone therapy in men treated for breast cancer are unknown.

32

Strength rating Weak

Weak

Strong

SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021

Assess for cardiovascular risk factors before commencing testosterone therapy. Assess men with known cardiovascular disease (CVD) for cardiovascular symptoms before testosterone therapy and with close clinical assessment and evaluation during treatment. Treat men with hypogonadism and pre-existing CVD, venous-thromboembolism or chronic cardiac failure, who require testosterone therapy with caution, by careful clinical monitoring and regular measurement of haematocrit (not exceeding 54%) and testosterone levels. Exclude a family history of venous-thromboembolism before starting testosterone therapy. Monitor testosterone, haematocrit at 3, 6 and 12 months after testosterone therapy initiation, and thereafter annually. A haematocrit > 54% should require testosterone therapy withdrawal and phlebotomy. Re-introduce testosterone therapy at a lower dose once the haematocrit has normalised and consider switching to topical testosterone preparations.

Strong Strong Weak

Strong Strong

*As for EAU risk groups for biochemical recurrence of localised or locally advanced prostate cancer (see EAU guidelines 2021 on prostate cancer)

4.

EPIDEMIOLOGY AND PREVALENCE OF SEXUAL DYSFUNCTION AND DISORDERS OF MALE REPRODUCTIVE HEALTH

4.1

Erectile dysfunction

Epidemiological data have shown a high prevalence and incidence of ED worldwide [169]. Among others, the Massachusetts Male Aging Study (MMAS) [170] reported an overall prevalence of 52% ED in noninstitutionalised men aged 40-70 years in the Boston area; specific prevalence for minimal, moderate, and complete ED was 17.2%, 25.2%, and 9.6%, respectively. In the Cologne study of men aged 30-80 years, the prevalence of ED was 19.2%, with a steep age-related increase from 2.3% to 53.4% [171]. The incidence rate of ED (new cases per 1,000 men annually) was 26 in the long-term data from the MMAS study [172] and 19.2 (mean follow-up of 4.2 years) in a Dutch study [173]. In a cross-sectional real-life study among men seeking first medical help for new-onset ED, one in four patients was younger than 40 years, with almost 50% of the young men complaining of severe ED [174]. Differences among these studies can be explained by differences in methodology, ages, and socio-economic and cultural status of the populations studied. The prevalence rates of ED studies are reported in Table 7.

4.2

Premature ejaculation

As evidenced by the highly discrepant prevalence rates reported in Table 8 [175], the method of recruitment for study participation, method of data collection and operational criteria can all greatly affect reported prevalence rates of premature ejaculation (PE). The major problem in assessing the prevalence of PE was the lack of a universally recognised definition at the time the surveys were conducted [176]. Vague definitions without specific operational criteria, different manners of sampling, and non-standardised data acquisition have led to heterogeneity in estimated prevalence [176-180]. The highest prevalence rate of 31% (men aged 18-59 years) was found by the National Health and Social Life Survey (NHSLS), which determines adult sexual behaviour in the USA [181]. Prevalence rates were 30% (18-29 years), 32% (30-39 years), 28% (40-49 years) and 55% (50-59 years). It is, however, unlikely that the PE prevalence is as high as 20-30% based on the relatively low number of men who seek medical help for PE. These high prevalence rates may be a result of the dichotomous scale (yes/ no) in a single question asking if ejaculation occurred too early, as the prevalence rates in European studies have been significantly lower [182]. Two separate observational, cross-sectional surveys from different continents found that overall prevalence of PE was 19.8 and 25.80%, respectively [183, 184]. Further stratifying these complaints into the classifications defined by Waldinger et al. [185], rates of lifelong PE were 2.3 and 3.18%, acquired PE 3.9 and 4.48%, variable PE 8.5 and 11.38% and subjective PE 5.1 and 6.4% [183, 184]. Both studies showed that men with acquired PE were more likely to seek treatment compared to men with lifelong PE. Treatment-seeking behaviour may have contributed to errors in the previously reported rates of PE, as it is possible that men with lifelong PE came to terms with their problem and did not seek treatment. The additional psychological burden of a new change in ejaculatory latency in acquired PE may have prompted more frequent treatment seeking [186]. Thus, it is likely that there is disparity between the incidence of the various PE sub-types in the general community and in men actively seeking treatment for PE [187, 188]. This disparity could be a further barrier to understanding the true incidence of each sub-type of PE. An approximately 5% prevalence of acquired PE and lifelong PE in the general population is consistent with epidemiological data indicating that around 5% of the population have an ejaculation latency of < 2 minutes [189]. SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021

33

4.3

Other ejaculatory disorders

4.3.1 Delayed ejaculation Due to its rarity and uncertain definitions, the epidemiology of delayed ejaculation (DE) is not clear [190]. However, several well-designed epidemiological studies have revealed that its prevalence is around 3% among sexually active men [181, 191]. According to data from the NHSLS, 7.78% of a national probability sample of 1,246 men aged 18-59 years reported inability achieving climax or ejaculation [181]. In a similar stratified national probability sample survey completed over 6 months among 11,161 men and women aged 16-44 years in Britain, 0.7% of men reported inability to reach orgasm [192]. In an international survey of sexual problems among 13,618 men aged 40–80 years from 29 countries, 1.1-2.8% of men reported that they frequently experience inability to reach orgasm [193]. Another study conducted in the United States, in a national probability sample of 1,455 men aged 57-85 years, 20% of men reported inability to climax and 73% reported that they were bothered by this problem. [194]. Considering the findings of these epidemiological studies and their clinical experiences, some urologists and sex therapists have postulated that the prevalence of DE may be higher among older men [195197]. Similar to the general population, the prevalence of men with DE is low among patients who seek treatment for their sexual problems. An Indian study that evaluated the data on 1,000 consecutive patients with sexual disorders who attended a psychosexual clinic demonstrated that the prevalence of DE was 0.6% and it was more frequent in elderly people with diabetes [198]. Nazareth et al. [199] evaluated the prevalence of International Classification of Diseases 10th edition (ICD-10) diagnosed sexual dysfunctions among 447 men attending 13 general practices in London, UK and found that 2.5% of the men reported inhibited orgasm during intercourse. Similar to PE, there are distinctions among lifelong, acquired and situational DE [200]. Although the evidence is limited, the prevalence of lifelong and acquired DE is estimated at 1 and 4%, respectively [201]. 4.3.2 Anejaculation and Anorgasmia Establishing the exact prevalence of anejaculation and anorgasmia is difficult since many men cannot distinguish between ejaculation and orgasm. The rarity of these clinical conditions further hampers the attempts to conduct epidemiological studies. In a report from the USA, 8% of men reported unsuccessfully achieving orgasm during the past year [181]. According to Kinsey et al. [202], 0.14% of the general population have anejaculation. The most common causes of anejaculation were spinal cord injury, diabetes mellitus and multiple sclerosis. Especially in most cases of spinal cord injury, medical assistance is the only way to ejaculate. While masturbation leads to the lowest rates of ejaculation, higher response rates can be obtained with penile vibratory stimulation or acetylcholine esterase inhibitors followed by masturbation in patients with spinal cord injury [203]. 4.3.3 Retrograde ejaculation Similar to anejaculation, it is difficult to estimate the true incidence of retrograde ejaculation (RE). Although RE is generally reported in 0.3-2% of patients attending fertility clinics [204], diabetes may increase these rates by leading to autonomic neuropathy. Autonomic neuropathy results in ED and ejaculatory dysfunctions ranging from DE to RE and anejaculation, depending on the degree of sympathetic autonomic neuropathy involved [205]. In 54 diabetic patients with sexual dysfunction, RE was observed with a 6% incidence [206]. In a controlled trial, RE was observed in 34.6% of diabetic men [207]. A more recent trial reported the rate of RE among 57 type-1-diabetes mellitus patients (aged 18-50 years) was at least 8.8% [208]. Retrograde ejaculation was also reported in studies of patients who had undergone transurethral resection of prostate (TURP) or open prostatectomy due to disrupted bladder neck integrity. A study of the effect of prostatectomy on QoL in 5,276 men after TURP, found that 68% reported post-surgical RE [209]. However, with the development of less invasive techniques, the incidence of RE decreases following the surgical treatment of LUTS [210-214]. 4.3.4 Painful ejaculation Painful ejaculation is a common but poorly understood clinical phenomenon, which is associated with sexual dysfunction. Several studies demonstrated its prevalence to range between 1 and 10% in the general population [215-217]; however, it may increase to 30-75% among men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) [218-222]. It should be noted that the design of most of these studies was not scientifically sound and the condition was probably under-reported due to the lack of an evidence-based definition and well-defined prognostic criteria. 4.3.5 Haemospermia The exact incidence and prevalence of haemospermia are difficult to elucidate due to a number of factors including its covert presentation, usually self-limiting nature and patient embarrassment. The symptom represents 1-1.5% of all urological referrals and occurs in all age groups, with a mean age of 37 years [223, 224]. In a PCa screening study of 26,126 men, aged ≥ 50 years or older than 40 with a history of PCa or of black ethnicity, haemospermia was found in 0.5% on entry to the trial [225].

34

SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021

4.4

Low sexual desire

The global prevalence of low sexual desire in men is 3-28% [193, 226, 227]. Low solitary and dyadic sexual desires, have been reported in 68% and 14% of men, respectively [228]. Also, low sexual desire has been observed as a common complaint in gay men, with a prevalence of 19-57% [229, 230]. Despite its relationship with age, low sexual desire has been reported among young men (18-29 years), with prevalence of 6-19% [181, 231, 232]. Table 7: Prevalence rates of erectile dysfunction [169] Date

Authors

Population

Response rate 81%

1993

Solstad et al. [233, 234]

439 men; random population sample (Denmark)

1994

Feldman et al. [170] *MMAS

1,290 men; 40% random population sample (United States)

40-70

Selfadministered questionnaire

1995

55% Panser et al. 2,155 men; [235] random population sample (United States)

40-79

Selfadministered questionnaire

1996

Helgason et al. [236]

319 men; random population sample (Sweden)

73%

50-80

Selfadministered questionnaire

1996

MacFarlane et al. [237]

1,734 men; random population sample (France)

86%

50-80

Selfadministered questionnaire

1996

Fugl-Meyer [226]

1,288 men; random population sample men (Sweden)

52%

18-74

Structured interview

SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021

Age Measurement (years) technique 51 Interview and selfadministered questionnaire

Principal findings

Correlates

Overall, 4% of men had ED as assessed by questionnaire, interviews identified a higher frequency of ED (40%) Overall, 52% of men had ED 17.2% of men had minimal ED 25.2% of men had moderate ED 9.6% of men had complete ED 1% ED in men aged 40-49 years 6% ED in men aged 50-59 years 22% ED in men aged 60-69 years 44% ED in men aged 70-79 years 3% ED in men aged 50–59 years 24% ED in men aged 60–69 years 49% ED in men aged 70–80 years 20% ED in men aged 50–59 years 33% ED in men aged 60–69 years 38% ED in men aged 70–80 years Overall, 5% of men had ED 3% ED in men aged 18–24 years 2% ED in men aged 25–34 years 2% ED in men aged 35–49 years 7% ED in men aged 50–65 years 24% ED in men aged 66–74 years

Not reported

Age

Age, Prostate cancer, Diabetes, Myocardial infarction, Diuretic use, Warfarin use, H2 receptor blocker use Age

Age

35

1999

Laumann et al. [181] *NHSLS

1,244 men; 70% random population sample (United States)

18-59

Structured interview

1999

Pinnock et al. [238]

427 men; random population sample (Australia)

69.8%

> 40

Selfadministered questionnaire

2000

Braun et al. [171] (COLOGNE Study)

8,000 men

56%

30-80

2001

Moreira et al. [239]

1,170 men; attending public places (heavy bias toward younger men) (Brazil)

91%

>18

Selfadministered questionnaire by mail (Cologne ED Questionnaire) Selfadministered questionnaire

2001

Meuleman et al. [240]

1,233 men; random population sample (the Netherlands)

70%

40-79

Selfadministered questionnaire

2001

Blanker et al. [216, 241]

1,688 men; random population sample (the Netherlands)

50%

50-75

Selfadministered questionnaire

36

Overall, 10% of men had ED (moderate plus severe) 7% ED in men aged 18–29 years 9% ED in men aged 30–39 years 11% ED in men aged 40–49 years 18% ED in men aged 50–59 years 6% ED in men aged 40–49 years 12% ED in men aged 50–59 years 41% ED in men aged 60–69 years 63% ED in men aged 70–79 years 81% ED in men aged 80+ years Prevalence of ED was 19.2%

Age, Race, Emotional stress, Urinary symptoms, Poor health, Low income

Overall, 14.7% of men had ED (moderate plus severe); 9.4% ED in men aged 18–39 years 15.5% ED in men aged 40–49 years 22.1% ED in men aged 50–59 years 37% ED in men aged 60–69 years 39.6% ED in men aged >70 years Overall, 13% of men had ED 6% ED in men aged 40–49 years 9% ED in men aged 50–59 years 22% ED in men aged 60–69 years 38% ED in men aged 70–79 years 3% ED in men aged 50–54 years 5% ED in men aged 55–59 years 11% ED in men aged 60–64 years 19% ED in men aged 65–69 years 26% ED in men aged 70–78 years

Age, Education, Racial origin, Diabetes, Hypertension, Depression

Age, Hypercholesterolemia,

Age, Hypertension, Diabetes, Pelvic surgery, LUTS

Age

Age, Smoking, Obesity, LUTS, COPD, Treatment for CV disease

SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021

2001

MartinMorales et al. [242]

2,476 men; 75% random population sample (Spain)

25-70

Selfadministered questionnaire and single question

2002

Moreira et al. [243]

602 men; 92% random population sample (Brazil)

40-70

Interview

2002

Moreira et al. [244]

342 men; 47.6% random population sample (Brazil)

40-70

Selfadministered questionnaire

2002

Morillo et al. 1,963 men; 82% [245] random population sample (Columbia, Venezuela and Ecuador) Richters 8,517 men; 69.4% et al. [246] random population sample (Australia)

> 40

Standardised questionnaire

16-59

Computerassisted telephone interview

2003

SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021

Overall, 12.1% of men had ED (single question) and 18.9% for questionnaire According to single question: 3.9% ED in men aged 25–39 years 6.3% ED in men aged 40–49 years 15.9% ED in men aged 50–59 years 32.2% ED in men aged 60–70 years IIEF identified milder ED, and single question identified more moderate and severe ED Overall, 14.4% of men had ED (moderate or severe) 9.9% ED in men aged 40–49 years 11.8% ED in men aged 50–59 years 31.7% ED in men aged 60–69 years Overall, 12.0% of men had ED (moderate or severe) 3.5% ED in men aged 40–49 years 16.7% ED in men aged 50–59 years 39.6% ED in men aged 60–69 years Overall, 19.8% of men had ED (moderate or severe)

Age, Hypertension, Diabetes, Cardiac disease, Pulmonary disease, Circulatory disease, Rheumatic disease, High cholesterol, Prostatic disease, Allergy, Medication “for nerves”, Sleeping tablets, Heavy smoking, Alcohol abuse

Age, Marital status, Diabetes, Depression, IPSS, Decreased physical activity

Age, Diabetes, Hypertension, Heavy smoking

Age, Diabetes, Hypertension, BPH

Overall, 9.5% of men Age had ED 4.3% ED in men aged 16–19 years 4.5% ED in men aged 20–29 years 5.1% ED in men aged 30–39 years 12.5% ED in men aged 40–49 years 19.2% ED in men aged 50–59 years

37

2003

Rosen et al. [247]

2004

Rosen et al. [248] *MALES

2004

Shiri et al. [249]

2,198 men; stratified birth cohort (Finland)

2005

Laumann et al. [193] *GSSAB

13,750 men; 19% random population sample (world)

2005

Moreira et al. [250]

2005

Moreira

750 men; 23% random population sample (Spain) 750 men; 17.4% random population sample (Germany)

et al. [251]

38

12,815 men; random population sample (multinational: United States, United Kingdom, France, Germany, the Netherlands, Italy, Spain) 27,839 men random population sample (multinational: United States, United Kingdom, Germany, France, Italy, Spain, Mexico, and Brazil)

36.8%

50-80

Selfadministered questionnaire (IIEF and DANPSS)

According to DANPSS: Overall, 48.9% of men had ED 30.8% ED in men aged 50-59 years 55.1% ED in men aged 60-69 years 76% ED in men aged 70-80 years

Age, LUTS, Diabetes, Hypertension, Cardiac disease, Hyperlipidemia, Tobacco use

US: 45%; UK: 48%; Germany: 45%; France: 48%; Italy: 53%; Spain: 50%; Mexico: 55% and Brazil: 51%. 70%

20-75

Random digit dialing and interviewed via computerassisted telephone interviewing. A standardised questionnaire

Overall prevalence of ED in the MALES sample was 16%

Age, Hypertension, Heart trouble or angina, High cholesterol, Diabetes, Depression or anxiety

50,60, and 70 at first survey 55, 65, and 75 at second survey 40-80

Selfadministered questionnaire at two separate time points, 5 years apart

48% of men had minimal ED 15.2% of men had moderate ED 13.2% of men had complete ED

Age, Diabetes, Hypertension, Heart disease, Cerebrovascular disease,Smoking

40-80

40-80

Telephone Overall: survey (random In Northern Europe, dialed digit) 13.3% had ED In Southern Europe, 12.9% had ED In non-European West, 20.6% had ED In Central/South America, 13.7% had ED In Middle East, 14.1% had ED In East Asia, 13.3% had ED In Southeast Asia, 28.1% had ED Telephone Overall, 12.7% had survey (random ED digit dialing)

Age

Age

Telephone Overall, 7.9% had ED Age survey (random digit dialing)

SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021

2005

Moreira Junior et al. [252]

471 men; random population sample (Brazil) 500 men; random population sample (Canada) 2,000 men; random population study (Brazil)

18%

40-80

Telephone Overall, 13.1% of survey (random men had ED digit dialing)

Age, Depression

2006

Brock et al. [253]

9.7%

40-80

Telephone Overall, 16% of men survey (random had ED digit dialing)

Age, Depression, Diabetes

2007

De Almeida Claro et al. [254]

Not reported

>20

Standardised interview with self-reported questionnaire (IIEF)

Overall, 1.7% of men had ED 0.2% ED in men aged 20-30 years 0.22% ED in men aged 31-40 years 1.0% ED in men aged 41-50 years 2.8% ED in men aged 51-60 years 7.0% ED in men aged > 61 years SelfOverall, 13.4% had administered self-reported ED questionnaire ED prevalence as (IIEF-5) defined by IIEF-5 score less than 17 was 32.4% According to single question: 4.2% ED in men aged 40-49 years 13.0% ED in men aged 50-59 years 30.1% ED in men aged 60-69 years 41.1% ED in men aged 70-79 years Telephone Overall, 32% of men survey (random had ED digit dialing)

Age

2007

Ahn et al. [255]

1,570 men; Not geographically reported stratified random population study

40-79

2008

Moreira et al. [256]

16.9%

40-80

2008

Chew et al. [257]

750 men; random population sample (Australia) 1,580 men; random population sample (Australia)

37.3%

>20

Postal survey Selfadministered questionnaire (IIEF-5)

Age, Marital status

SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021

15.7% ED in men aged 20-29 years 8.7% ED in men aged 30-39 years 12.9% ED in men aged 40-49 years 31.6% ED in men aged 50-59 years 52.4% ED in men aged 60-69 years 69.4% ED in men aged 70-79 years 68.2% ED in men aged > 80 years

Age, Single status, Low income, Diabetes, Hypertension, Hyperlipidemia, Heart disease, Musculoskeletal disorders, Alcohol, Depression, Coffee intake

Age

39

2008

Teles et al. [258]

3,067 men; random population sample (Portugal)

81.3%

40-69

2008

Moreira et al. [259]

750 men; random population

17%

40-80

2009

Laumann et al. [260]

2009

Buvat et al. [261]

2010

Corona et al. [262]

2016

Oyelade et al. [263]

2017

Cayan et al. [264]

2017

Quilter et al. Randomly [265] selected age-stratified populationbased sample of 2,000 men (New Zealand)

40

Overall, 48.1% of men had ED 29% ED in men aged 40-49 years 50% ED in men aged 50-59 years 74% ED in men aged 60-69 years Telephone Overall, 17.8% of survey (random men had ED digit dialing)

Age, Diabetes, Cardiac insufficiency, Psychiatric illness

40-80

Telephone Overall, 22.5% of survey (random men had ED digit dialing)

Age, Depression

40-80

Telephone Overall, 15% of men survey (random had ED digit dialing)

Age

40%

40-80

Selfadministered questionnaire

Age, Depression, LUTS, Cardiovascular disease, Diabetes, Obesity

99%

30-80

Selfadministered questionnaire (IIEF-5)

Overall, 30% of men had ED 6% ED in men aged 40-49 years 19% ED in men aged 50-59 years 38% ED in men aged 60-69 years 64% ED in men 70 and over General prevalence of ED was 58.9%

Nonreported

> 40

Selfadministered questionnaire (IIEF-5)

Age, Diabetes, Hypertension, Atherosclerosis, Dyslipidaemia, LUTS, Educational status, Monthly income

30%

40-70

Prevalence of ED was calculated as 33% among all men aged ≥ 40 years. ED prevalence rates were 17% for 40-49 years, 35.5% for 50-59 years, 68.8% for 60-69 years, and 82.9% for ≥ 70 years Self-reported Prevalence of ED was erectile 42% (22% mild, 10% function (IIEF-5) mild to moderate, and a single6% moderate, and question self4% severe) assessment tool.

sample (United Kingdom) 742 men; 9% random population sample (United States) 750 men; 23.8% random population sample (France) 3,369 men; random population study (Europe: Italy, Belgium, United Kingdom, Spain, Poland, Hungary, Estonia) 241 men; random sampling crosssectional population based survey (Nigeria) 2,760 men; random population study (Turkey)

Selfadministered questionnaire, including IIEF

Age

Age, Hypertension, Use of antihypertensive drugs, Diabetes mellitus, Heart disease

Age, Anxiety or depression

SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021

2020

Calzo et al. [266]

2,660 sexually active men (USA)

18-31

Selfadministered questionnaire (IIEF-5)

Prevalence of mild ED was 11.3% and moderate-to-severe ED was 2.9%

Demographic (age; marital status) Metabolic (body mass index; waist circumference; history of diabetes, hypertension, hyperch olesterolaemia) Mental health (depression, anxiety, antidepressant, tranquiliser use)

Four baseline studies estimating the prevalence of Erectile Dysfunction: MMAS = the Massachusetts Male Aging Study; NHSLS = the National Health of Social Life Survey; MALES = the multi-national men’s attitudes to life events and sexuality; GSSAB = Global Study of Sexual Attitudes and Behaviours. BPH = Benign Prostate Hyperplasia; COPD = Chronic Obstructive Pulmonary Disease; ED = Erectile Dysfunction; IIEF = International Index of Erectile Function; IPSS = International Prostate Symptom Score; LUTS = Lower urinary tract symptoms. Table 8: Date 1998

1999

2002

2004 2004 2005

2005 2005

The prevalence rates of premature ejaculation [175]

Authors

Method of Data Method of Collection Recruitment Dunn et al. Mail General practice [267] registers - random stratification Laumann et al. Interview NA (NHSLS) [181]

Fugl-Meyer and FuglMeyer [268] Rowland et al. [269] Nolazco et al. [270] Laumann et al. [193]

Interview

Population register

Operational Criteria Having difficulty with ejaculating prematurely Climaxing/ ejaculating too rapidly during the past 12 months NA

Mailed questionnaire Interview

Internet panel

DSM IV

16.3%

1,158

Invitation to outpatient clinic Random (systematic) sampling

Ejaculating fast or prematurely Reaching climax too quickly during the past 12 months DSM IV

28.3%

2,456

23.75% (4.26% frequently)

13,618

21.2%

12,558

Often ejaculating in less than < 2 minutes Control over ejaculation, distress Self-report premature ejaculation DSM III Control Distress

9.5%

601

22.7%

12,133

50%

73

16% 26% 27% 27%

3,816

Telephonepersonal interview/mailed questionnaires Basile Fasolo Clinician-based Invitation to et al. [271] outpatient clinic Stulhofer et al. Interview Stratified sampling [272]

2007

Porst et al. (PEPA) [182]

2008

Shindel et al. [273]

2009

Brock et al. [274]

telephone interview

2010

Traeen and Stigum [232]

Mailed questionnaire + internet

Web-based survey Self-report Questionnaire

Internet panel

Male partners of infertile couples under evaluation Web-based survey

Web interview + Randomisation

SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021

Prevalence Rate 14% (past 3 mo) 31% (lifetime)

Number of Men 617 618

31%

1,410

9%

1,475

11,746 + 1,671

41

2010

Son et al. [275] Questionnaire

2010

Amidu et al. [276] Liang et al. [277] Park et al. [278] Vakalopoulos et al. [279] Hirshfeld et al. [229]

DSM IV

18.3%

600

Questionnaire

Internet panel (age < 60 years) NA

NA

64.7%

255

NA

NA

ISSM

15.3%

1,127

Mailed questionnaire One-on-one survey Web-based survey

Stratified sampling

Suffering from PE 27.5%

2,037

Population-based cohort Online advertisement in the United States and Canada

58.43% 17.7% 34%

522

Christensen Interview + et al. [280] questionnaire Serefoglu et al. Interview [183]

Population register (random) Stratified sampling

EED ISSM lifelong PE Climaxing/ ejaculating too rapidly during the past 12 months NA

7%

5,552

2011

Son et al. [281] Questionnaire

Internet panel

2011

Tang and Khoo [282] Mialon et al. [283]

Interview

Primary care setting

Mailed questionnaire

2012

Shaeer and Shaeer [284]

Web-based survey

Convenience sampling (age 18-25 years) Online advertisement in Arabic countries

2012

Shindel et al. [285]

Web-based survey

2012

McMahon et al. [286]

2012

Lotti et al. [287] Zhang et al. [288]

Computer assisted interviewing, online, or in-person selfcompleted Interview

2010 2010 2010 2010

2011 2011

2012

2013

Interview

2013

Lee et al. [289] Interview

2013

Gao et al. [184]

2013

Hwang et al. [290]

42

Interview

Complaining 20.0% about ejaculating prematurely Estimated 10.5% IELT 9 40.6%

Control over 11.4% ejaculation Distress Ejaculate before 83.7% the person wishes to ejaculate at least sometimes 8-12% Online advertisement PEDT > 9 targeted to MSM + distribution of invitation to organisations catering to MSM PEDT > 11 16% NA Self-Reported 13% (always/nearlyalways)

Men seeking medical care for infertility Random stratified sample of married men aged 30-60 Stratified random sampling

7,001

2,593

334

207 2,507

804

1,769

4,997

PEDT > 9

15.6%

244

Self-reported premature ejaculation PEDT > 11 Self-Reported IELT 11

1,035 3,016

12.1%

SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021

2013

Vansintejan et al. [291]

Web Based survey

2013

Shaeer et al. [292]

Web Based survey

2016

Karabakan [293]

2017

Gao et al. [294]

Online and flyer advertisements to Belgian men who have sex with men (Only HIV+ men in this study) Targeting Englishspeaking men aged > 18 years, living most of their lives in the USA, regardless

of personal interests and web browsing preferences Interview (heavy Targeting police bias toward academy students younger men) aged 24-30 years who applied for routine urological examination Field survey with Comprising men face-to-face aged 20-68 years interviews in five cities in the Anhui province

IPE score < 50% of total possible

4%

72

ISSM definition [179] PEDT Unfiltered selfreported Filtered selfreported

6.3%

1133

49.6% 77.6% 14.4%

PEDT > 10

9.2%

1000

Self-estimated IELT

Lifelong PE 10.98% Acquired PE 21.39%

1239

DMS = Diagnostic and Statistical Manual of Mental Disorders; NA = not applicable; ISSM = International Society for Sexual Medicine; PEDT = Premature Ejaculation Diagnostic Tool; IELT = intravaginal ejaculatory latency time; IPE = Index of Premature Ejaculation; mo = months.

5.

MANAGEMENT OF ERECTILE DYSFUNCTION

5.1

Definition and classification

Penile erection is a complex physiological process that involves integration of both neural and vascular events, along with an adequate endocrine milieu. It involves arterial dilation, trabecular smooth muscle relaxation and activation of the corporeal veno-occlusive mechanism [295]. Erectile dysfunction is defined as the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance [296]. Erectile dysfunction may affect psychosocial health and have a significant impact on the QoL of patients and their partner’s [170, 297-299]. There is established evidence that the presence of ED increases the risk of future CV events including myocardial infarction, cerebrovascular events, and all-cause mortality, with a trend towards an increased risk of cardiovascular mortality [300]. Therefore, ED can be an early manifestation of coronary artery and peripheral vascular disease and should not be regarded only as a QoL issue, but also as a potential warning sign of CVD [301-304]. A cost analysis showed that screening men presenting with ED for CVD represents a cost-effective intervention for secondary prevention of both CVD and ED, resulting in substantial cost savings relative to identification of CVD at the time of presentation [305]. Erectile dysfunction is commonly classified into three groups based on aetiology: organic, psychogenic and mixed ED. However, this classification should be used, with caution as most cases are actually of mixed aetiology. It has therefore been suggested to use the terms “primary organic” or “primary psychogenic”.

5.2

Risk factors

Erectile dysfunction is associated with unmodifiable and modifiable common risk factors including age, diabetes mellitus, dyslipidaemia, hypertension, CVD, BMI/obesity/waist circumference, MetS, hyperhomocysteinemia, lack of exercise, and smoking (a positive dose-response association between quantity and duration of smoking has been demonstrated) [298, 302, 306-313]. Furthermore, an association between ED status and pharmaco-therapeutic agents for CVD (e.g., thiazide diuretics and β-blockers, except nebivolol), exert detrimental effects on erectile function, whereas newer drugs (i.e., angiotensin-converting enzymeinhibitors, angiotensin-receptor-blockers and calcium-channel-blockers) have neutral or even beneficial effects

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43

[302, 314, 315]. Atrial fibrillation [316], hyperthyroidism [20], vitamin D deficiency [317, 318], hyperuricemia [319], depression [320], chronic kidney disease [313], rheumatic disease [321] and chronic obstructive pulmonary disease [322] have also been reported as risks factors. Available data do not confirm a clear association between ED and hypothyroidism and hyperprolactinaemia [20]. Further epidemiological data have also highlighted other potential risk factors associated with ED including sleep disorders [323], obstructive sleep apnoea [324], psoriasis [325-327], gouty arthritis [328] and ankylosing spondylitis [329], non-alcoholic fatty liver disease [330], other chronic liver disorders [331], chronic periodontitis [332], open-angle glaucoma [333], inflammatory bowel disease [334], chronic fatigue syndrome [335] and allergic rhinitis [336]. Insufficient data are currently available to correlate primarily organic or primarily psychogenic ED with SARS-CoV-2 infection associated disease (COVID-19) [337, 338]. Erectile dysfunction is also frequently associated with other urological conditions and procedures (Table 9). Epidemiological studies have demonstrated consistent evidence for an association between LUTS/BPH and sexual dysfunction, regardless of age, other co-morbidity and lifestyle factors [339]. The Multinational Survey on the Aging Male study, performed in the USA, France, Germany, Italy, Netherlands, Spain, and the UK, systematically investigated the relationship between LUTS and sexual dysfunction in > 12,000 men aged 50-80 years. In the 83% of men who were reported to be sexually active, the overall prevalence of LUTS was 90%, with an overall 49% prevalence of ED and a reported complete absence of erections in 10% of patients. The overall prevalence of ejaculatory disorders was 46% [247]. Regardless of the technique used, surgery for BPH-LUTS had no significant impact on erectile function. A post-operative improvement of erectile function was even found depending on the degree of LUTS improvement [340, 341]. An association has been confirmed between ED and CP/CPPS [342], and bladder pain syndrome/interstitial cystitis (BPS/IC), mostly in younger men [343]. An association between ED and PE has also been demonstrated (see Section 6.2) [344]. An increased risk of ED is reported following transrectal ultrasound (TRUS)-guided prostate biopsy [345] and after open urethroplasty, especially for correction of posterior strictures [346], with recent findings emphasising the importance of patient-reported outcome measures (PROMs) in urethral reconstructive surgery to better report actual sexual function outcomes [347, 348]. Table 9: Urological conditions associated with ED Urological Condition LUTS/BPH [339]

Surgery for BPH/LUTS (TURP, laser, open, laparoscopic, etc.) [340] Chronic Prostatitis/Chronic Pelvic Pain Syndrome [342] Bladder Pain Syndrome/Interstitial Cystitis [343]

Premature Ejaculation [345] Urethroplasty surgery for posterior urethral strictures [346]

Association with ED Depending on the severity of LUTS and patients’ age/population characteristics: Odds ratio (OR) of ED among men with LUTS/BPH ranges from 1.52 to 28.7 and prevalence ranges from 58% to 80% Overall, absence of significant variations in terms of erectile function scores after surgery Prevalence of ED among patients with CP/CPPS 29% [24%-33%, 95%CI], Range: 11% - 56% among studies OR of BPS/IC among patients with ED. Overall: OR (adjusted) = 1.75 [1.12 – 2.71, 95%CI] Age > 60: OR (adjusted) = 1.07 [0.41 – 2.81, 95%CI] Age 40-59: OR (adjusted) = 1.44 [1.02 – 2.12, 95%CI] Age 18-39: OR (adjusted) = 10.40 [2.93 – 36.94, 95%CI] OR of ED among patients with PE = 3.68 [2.61 – 5.68, 95%CI] OR of ED after posterior urethroplasty = 2.51 [1.82 – 3.45, 95%CI]

CI = confidence interval; OR = odds ratio; TURP = transurethral resection of the prostate; ED = erectile dysfunction; BPS/IC = bladder pain syndrome/interstitial cystitis; LUTS = lower urinary tract symptoms.

5.3

Pathophysiology

The pathophysiology of ED may be vasculogenic, neurogenic, anatomical, hormonal, drug-induced and/or psychogenic (Table 10) [295]. In most cases, numerous pathophysiological pathways can co-exist and may all negatively impact on erectile function. The proposed ED etiological and pathophysiological division should not be considered prescriptive. In most cases, ED is associated with more than one pathophysiological factor and very often, if not always, will have a psychological component. Likewise, organic components can negatively affect erectile function with different pathophysiological effects. Therefore, Table 10 must be considered for diagnostic classifications only (along with associated risk factors for each subcategory). 44

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Table 10: Pathophysiology of ED Vasculogenic Recreational habits (i.e., cigarette smoking) Lack of regular physical exercise Obesity Cardiovascular diseases (e.g., hypertension, coronary artery disease, peripheral vasculopathy) Type 1 and 2 diabetes mellitus; hyperlipidaemia; metabolic syndrome; hyperhomocysteinemia Major pelvic surgery (e.g., radical prostatectomy) or radiotherapy (pelvis or retroperitoneum) Neurogenic Central causes Degenerative disorders (e.g., multiple sclerosis, Parkinson’s disease, multiple atrophy, etc.) Spinal cord trauma or diseases Stroke Central nervous system tumours Peripheral causes Type 1 and 2 diabetes mellitus Chronic renal failure, chronic liver failure Polyneuropathy Surgery (major surgery of pelvis/retroperitoneum) or radiotherapy (pelvis or retroperitoneum) Surgery of the urethra (urethral stricture, open urethroplasty, etc.) Anatomical or structural Hypospadias, epispadias; micropenis Phimosis Peyronie’s disease Penile cancer (other tumours of the external genitalia) Hormonal Diabetes mellitus; Metabolic Syndrome; Hypogonadism (any type) Hyperthyroidism Hyper- and hypocortisolism (Cushing’s disease, etc.) Panhypopituitarism and multiple endocrine disorders Mixed pathophysiological pathways Chronic systemic diseases (e.g., diabetes mellitus, hypertension, metabolic syndrome, chronic kidney disease, chronic liver disorders, hyperhomocysteinemia, hyperuricemia, chronic obstructive pulmonary disease, rheumatic disease) Psoriasis, gouty arthritis, ankylosing spondylitis, non-alcoholic fatty liver disease, chronic periodontitis, open-angle glaucoma, inflammatory bowel disease, chronic fatigue syndrome, allergic rhinitis, obstructive sleep apnoea, depression Iatrogenic causes (e.g. TRUS-guided prostate biopsy) Drug-induced Antihypertensives (i.e., thiazidediuretics, beta-blockers)* Antidepressants (e.g., selective serotonin reuptake inhibitors, tricyclics) Antipsychotics Antiandrogens (GnRH analogues and antagonists; 5-ARIs) Recreational drugs (e.g., heroin, cocaine, marijuana, methadone, synthetic drugs, anabolic steroids, excessive alcohol intake) Psychogenic Generalised type (e.g., lack of arousability and disorders of sexual intimacy) Situational type (e.g., partner-related, performance-related issues or due to distress) Trauma Penile fracture Pelvic fractures GnRH = gonadotropin-releasing hormone; 5-ARIs = 5α-reductase inhibitors. *A symmetry analysis showed that cardiovascular drugs do not strongly affect the risk of subsequently being prescribed as anti-erectogenic drug. The analysis only assessed the short-term risk [356].

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5.3.1 Pelvic surgery and prostate cancer treatment Pelvic surgery, especially for oncological disease (e.g., radical prostatectomy (RP) [357] or radical cystectomy [358] and colorectal surgery [359]), may have a negative impact on erectile function and overall sexual health. The most relevant causal factor is a lesion occurring in the neurovascular bundles that control the complex mechanism of the cavernous erectile response, whose preservation (either partial or complete) during surgery eventually configures the so-called nerve-sparing (NS) approach [360]. Therefore, surgery resulting in damage of the neurovascular bundles, results in ED, although NS approaches have been adopted over the last few decades. This approach is applicable to all types of surgery that are potentially harmful to erectile function, although to date, only the surgical treatment of PCa has enough scientific evidence supporting its potential pathophysiological association with ED [361-363]. However, even non-surgical treatments of PCa (i.e., radiotherapy, or brachytherapy) can be associated with ED [364, 365]. The concept of active surveillance for the treatment of PCa was developed to avoid over-treatment of non-significant localised low-risk diseases, while limiting potential functional adverse effects (including ED). However, it is interesting that data suggest that even active surveillance has a detrimental impact on erectile function (and sexual well-being as a whole) [366-368]. To date, some of the most robust data on PROMs including erectile function, comparing treatments for clinically localised PCa come from the Prostate Testing for Cancer and Treatment (ProtecT) trial, in which 1,643 patients were randomised to active treatment (either RP or RT) and active monitoring and were followed-up for 6 years [369]. Sexual function, including erectile function, and the effect of sexual function on QoL were assessed with the Expanded Prostate Cancer Index Composite with 26 items (EPIC-26) instrument [370, 371]. At baseline, 67% of men reported erections firm enough for sexual intercourse but this fell to 52% in the active monitoring group, 22% in the RT group, and 12% in the RP group, at 6-months’ assessment. The worst trend over time was recorded in the RP group (with 21% erections firm enough for intercourse after 3 years vs. 17% after 6 years). In the RT group, the percentage of men reporting erections firm enough for intercourse increased between 6 and 12 months, with a subsequent decrease to 27% at 6-years assessment. The percentage declined over time on a yearly basis in the active monitoring group, with 41% of men reporting erections firm enough for intercourse at 3 years and 30% at 6 year evaluations [369]. Radical prostatectomy (open, laparoscopic or robot-assisted) is a widely performed procedure with a curative intent for patients presenting with clinically localised intermediate- or high-risk PCa and a life expectancy of > 10 years based on health status and co-morbidity [372, 373]. This procedure may lead to treatment-specific sequelae affecting health-related QoL. Men undergoing RP (any technique) should be adequately informed before the operation that there is a significant risk of sexual changes other than ED, including decreased libido, changes in orgasm, anejaculation, Peyronie’s-like disease, and changes in penile length [363, 365]. These outcomes have become increasingly important with the more frequent diagnosis of PCa in both younger and older men [374-376]. Research has shown that 25-75% of men experience post-RP ED [377], even though these findings had methodological flaws; in particular, the heterogeneity of reporting and assessment of ED among the studies [361, 378]. Conversely, the rate of unassisted post-operative erectile function recovery ranged between 20 and 25% in most studies. These rates have not substantially improved or changed over the past 17 years, despite growing attention to post-surgical rehabilitation protocols and refinement of surgical techniques [378-380]. Overall, patient age, baseline erectile function and surgical volume, with the consequent ability to preserve the neurovascular bundles, seem to be the main factors in promoting the highest rates of post-operative potency [362, 375, 377, 381]. Patients being considered for nerve-sparing RP (NSRP) should ideally be potent preoperatively [374, 375]. The recovery time following surgery is of clinical importance in terms of post-operative recovery of erectile function. Available data confirm that post-operative erectile function recovery can occur up to 48 months after RP [382]. Likewise, it has been suggested that post-operative therapy (any type) should be commenced as soon as possible after the surgical procedure [374, 377], although evidence suggests that the number of patients reporting return of spontaneous erectile function has not increased. In terms of the effects of surgical interventions (e.g., robot-assisted RP [RARP] vs. other types of surgery), data are still conflicting. An early systematic review showed a significant advantage in favour of RARP in comparison with open retropubic RP in terms of 12-month potency rates [383], without significant differences between laparoscopic RP and RARP. Some recent reports confirm that the probability of erectile function recovery is about twice as high for RARP compared with open RP [384]. More recently, a prospective, controlled, nonrandomised trial of patients undergoing RP in 14 Swedish centres comparing RARP versus open retropubic RP, showed a small improvement in erectile function after RARP [385]. Conversely, a randomised controlled phase 3 study of men assigned to open RP or RARP showed that the two techniques yielded similar functional outcomes at 12 weeks [386]. More controlled prospective well-designed studies, with longer follow-up, are

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necessary to determine if RARP is superior to open RP in terms of post-operative ED rates [387]. To overcome the problem of heterogeneity in the assessment of erectile function, for which there is variability in terms of the PROMs used (e.g., International Index of Erectile Function [IIEF], IIEF-5, Expanded Prostate Cancer Index Composite with 26 items [EPIC 26], Sexual Health Inventory for Men, etc.) to measure potency or erectile function, the criteria used to define restoration of erectile function should be re-evaluated utilising objective and validated thresholds (e.g., normalisation of scores or return to baseline erectile function) [361]. Erectile dysfunction is also a common problem after both external beam radiation therapy (EBRT) and brachytherapy for PCa. A systematic review and meta-analysis including men treated with EBRT (65%), brachytherapy (31%) or both (4%) showed that the post-treatment prevalence of ED was 34% at 1 year and 57% at 5.5 years [388, 389]. Similar findings have been reported for stereotactic radiotherapy with 26-55% of previously sexually functioning patients reporting ED at 5 years [390]. Recently other modalities have emerged as potential therapeutic options in patients with clinically-localised PCa, including whole gland and focal (lesion-targeted) treatments, to ablate tumours selectively while limiting sexual toxicity by sparing the neurovascular bundles. These include high-intensity focused US (HIFU), cryotherapeutic ablation of the prostate (cryotherapy), focal padeliporfin-based vascular-targeted photodynamic therapy and focal radiation therapy (RT) by brachytherapy or CyberKnife®. All these approaches have a lessnegative impact on erectile function, although they all lack robust mid- and long-term oncological outcomes, and prospective randomised controlled studies are needed to compare their functional and oncological outcomes [391, 392]. 5.3.2

Summary of evidence on the epidemiology/aetiology/pathophysiology of ED

Summary of evidence Erectile dysfunction is common worldwide. Erectile dysfunction shares common risk factors with cardiovascular disease. Lifestyle modification (regular exercise and decrease in BMI) can improve erectile function. Erectile dysfunction is a symptom, not a disease. Some patients may not be properly evaluated or receive treatment for an underlying disease or condition that may be causing ED. Erectile dysfunction is common after RP, irrespective of the surgical technique used. Erectile dysfunction is common after external radiotherapy and brachytherapy. Erectile dysfunction is less common after cryotherapy and high-intensity focused US.

5.4

LE 2b 2b 1b 4 2b 2b 2b

Diagnostic evaluation (basic work-up)

5.4.1 Medical and sexual history The first step in evaluating ED is always a detailed medical and sexual history of patients and, when available, their partners [393]. It is important to establish a relaxed atmosphere during history-taking. This will make it easier to ask questions about erectile function and other aspects of the patient’s sexual history; and to explain the diagnosis and therapeutic approach to the patient and their partner. Figure 3 lists the minimal diagnostic evaluation (basic work-up) in patients with ED. The sexual history must include information about previous and current sexual relationships, current emotional status, onset and duration of the erectile problem, and previous consultations and treatments. The sexual health status of the partner(s) (when available) can also be useful. A detailed description should be made of the rigidity and duration of both sexually-stimulated and morning erections and of problems with sexual desire, arousal, ejaculation, and orgasm [394, 395]. Validated psychometric questionnaires, such as the IIEF [85] or its short version (i.e., Sexual Health Inventory for Men; SHIM) [85], help to assess the different sexual function domains (i.e. sexual desire, erectile function, orgasmic function, intercourse satisfaction, and overall satisfaction), as well as the potential impact of a specific treatment modality. Similarly, structured interviews allow the identification and quantification of the different underlying factors affecting erectile function [396]. Psychometric analyses also support the use of the Erectile Hardness Score (EHS) for the assessment of penile rigidity in practice and in clinical trials research [397]. In cases of depressive mood, clinicians may use the Beck Depressive Inventory [398], which is one of the most recognised self-reported measures in the field, takes approximately 10 minutes to complete, and assigns the patient to a specific level of depression (varying from “normal mood” to “extreme depression”). Patients should always be screened for symptoms of possible hypogonadism (testosterone deficiency), including decreased energy and libido, and fatigue; potential cognitive impairment may be also observed in association with hypogonadism (see Sections 3.5 and 3.6), as well as for LUTS. In this regard,

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although LUTS/BPH in themselves do not represent contraindications to treatment for LOH, screening for LUTS severity is clinically relevant [7]. 5.4.2 Physical examination Every patient must be given a physical examination focused on the genitourinary, endocrine, vascular and neurological systems [399, 400]. A physical examination may reveal unsuspected diagnoses, such as Peyronie’s disease, pre-malignant or malignant genital lesions, prostatic enlargement or irregularity/nodularity, or signs and symptoms suggestive of hypogonadism (e.g., small testes or alterations in secondary sexual characteristics). Assessment of previous or concomitant penile abnormalities (e.g., hypospadias, congenital curvature, or Peyronie’s disease with preserved rigidity) during the medical history and the physical examination is mandatory. Blood pressure and heart rate should be measured if they have not been assessed in the previous 3-6 months. Likewise either BMI calculation or waist circumference measurement should be undertaken to assess patients for comorbid conditions (e.g., MetS). 5.4.3 Laboratory testing Laboratory testing must be tailored to the patient’s complaints and risk factors. Patients should undergo a fasting blood glucose or haemoglobin A1c and lipid profile measurement if they have not been assessed in the previous 12 months. Hormonal tests should include early morning total testosterone in a fasting state. The bioavailable or calculated-free testosterone values may sometimes be needed to corroborate total testosterone measurements. However, the threshold of testosterone required to maintain an erection is low and ED is usually a symptom of more severe cases of hypogonadism (see Sections 3.5 and 3.6) [20, 53, 401-403]. Additional laboratory tests may be considered in selected patients with specific signs and associated symptoms (e.g., PSA) [404], prolactin and luteinising hormone [405]). Although physical examination and laboratory evaluation of most men with ED may not reveal the exact diagnosis, clinical and biochemical evaluation presents an opportunity to identify comorbid conditions [400].

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Figure 3: Minimal diagnostic evaluation (basic work-up) in patients with ED Patient with ED (self-reported)

Medical and psychosexual history (use of validated instruments, e.g. IIEF)

Identify other sexual problems, (not ED)

Identify common causes of ED

Identify reversible risk factors for ED

Assess psychosocial status

Focused physical examination

Penile deformities

Prostatic disease

Signs of hypogonadism

Cardiovascular and neurological status

Laboratory tests

Glucose-lipid profile (if not assessed in the last 12 months)

Total testosterone (morning sample) if indicated, bio-available or free testosterone

ED = erectile dysfunction; IIEF = International Index of Erectile Function. 5.4.4 Cardiovascular system and sexual activity: the patient at risk Patients who seek treatment for sexual dysfunction have a high prevalence of CVDs. Epidemiological surveys have emphasised the association between cardiovascular/metabolic risk factors and sexual dysfunction in both men and women [406]. Overall, ED can improve the sensitivity of screening for asymptomatic CVD in men with diabetes [407, 408]. Erectile dysfunction significantly increases the risk of CVD, coronary heart disease and stroke. Furthermore, the results of a recent prospective cohort study showed that ED is an independent predictor for incident atrial fibrillation [409]. All of these cause mortality and the increase is probably independent of conventional cardiovascular risk factors [301, 302, 410, 411]. Longitudinal data from an observational population-based study of 965 men without CVD showed that younger men (especially those < 50 years) with transient and persistent ED have an increased Framingham CVD risk [412]. The EAU Guidelines for diagnosing and treating men with ED have been adapted from previously published recommendations from the Princeton Consensus conferences on sexual dysfunction and cardiac risk [413]. The Princeton Consensus (Expert Panel) Conference is dedicated to optimising sexual function and preserving cardiovascular health [413-415]. Accordingly, patients with ED can be stratified into three cardiovascular risk categories (Table 11), which can be used as the basis for a treatment algorithm for initiating or resuming sexual activity (Figure 3). It is also possible for the clinician to estimate the risk of sexual activity in most patients from their level of exercise tolerance, which can be determined when taking the patient’s history [353].

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Table 11: Cardiac risk stratification (based on 2nd and 3rd Princeton Consensus) [413, 415] Low-risk category Asymptomatic, < 3 risk factors for CAD (excluding sex) Mild, stable angina (evaluated and/or being treated) Uncomplicated previous MI LVD/CHF (NYHA class I or II) Post-successful coronary revascularisation

Intermediate-risk category > 3 risk factors for CAD (excluding sex) Moderate, stable angina

High-risk category High-risk arrhythmias

Recent MI (> 2, < 6 weeks) LVD/CHF (NYHA class III) Non-cardiac sequelae of atherosclerotic disease (e.g., stroke, peripheral vascular disease)

Recent MI (< 2 weeks) LVD/CHF (NYHA class IV) Hypertrophic obstructive and other cardiomyopathies

Controlled hypertension Mild valvular disease

Unstable or refractory angina

Uncontrolled hypertension Moderate-to-severe valvular disease

CAD = coronary artery disease; CHF = congestive heart failure; LVD = left ventricular dysfunction; MI = myocardial infarction; NYHA = New York Heart Association. Figure 4: Treatment  algorithm for determining level of sexual activity according to cardiac risk in ED (based on 3rd Princeton Consensus) [413]

Sexual inquiry of all men

ED confirmed

Exercise abilitya

Low risk

High risk

Intermediate risk Elective risk assessment Stress testb

Pass

Low risk

Advice, treat ED

Fail

High risk

Cardiologist

a

 exual activity is equivalent to walking 1 mile on the flat in 20 minutes or briskly climbing two flights of stairs in S 10 seconds. b Sexual activity is equivalent to 4 minutes of the Bruce treadmill protocol.

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5.4.4.1 Low-risk category The low-risk category includes patients who do not have any significant cardiac risk associated with sexual activity. Low-risk is typically implied by the ability to perform exercise of modest intensity, which is defined as, > 6 metabolic equivalents of energy expenditure in the resting state, without symptoms. According to current knowledge of the exercise demand or emotional stress associated with sexual activity, low-risk patients do not need cardiac testing or evaluation before initiation or resumption of sexual activity or therapy for sexual dysfunction. 5.4.4.2 Intermediate- or indeterminate-risk category The intermediate- or indeterminate-risk category consists of patients with an uncertain cardiac condition or patients whose risk profile requires testing or evaluation before the resumption of sexual activity. Based upon the results of testing, these patients may be moved to either the high- or low-risk group. A cardiology consultation may be needed in some patients to help the primary physician determine the safety of sexual activity. 5.4.4.3 High-risk category High-risk patients have a cardiac condition that is sufficiently severe and/or unstable for sexual activity to carry a significant risk. Most high-risk patients have moderate-to-severe symptomatic heart disease. High-risk individuals should be referred for cardiac assessment and treatment. Sexual activity should be stopped until the patient’s cardiac condition has been stabilised by treatment, or a decision made by the cardiologist and/or internist that it is safe to resume sexual activity.

5.5

Diagnostic Evaluation (advanced work-up)

Most patients with ED can be managed based on the basis of medical and sexual history; conversely, some patients may need specific diagnostic tests (Tables 12 and 13). 5.5.1 Nocturnal penile tumescence and rigidity test The nocturnal penile tumescence and rigidity (NPTR) test applies nocturnal monitoring devices that measure the number of erectile episodes, tumescence (circumference change by strain gauges), maximal penile rigidity, and duration of nocturnal erections. The NPTR assessment should be performed on at least two separate nights. A functional erectile mechanism is indicated by an erectile event of at least 60% rigidity recorded on the tip of the penis that lasts for > 10 minutes [416]. Nocturnal penile tumescence and rigidity monitoring is an attractive approach for objectively differentiating between organic and psychogenic ED (patients with psychogenic ED usually have normal findings in the NPTR test). However, many potential confounding factors (e.g., situational) may limit its routine use for diagnostic purposes [417]. 5.5.2 Intracavernous injection test The intracavernous injection test gives limited information about vascular status. A positive test is a rigid erectile response (unable to bend the penis) that appears within 10 minutes after the intracavernous injection and lasts for 30 minutes [418]. Overall, the test is inconclusive as a diagnostic procedure and a duplex Doppler study of the penis should be requested, if clinically warranted. 5.5.3 Dynamic duplex ultrasound of the penis Dynamic duplex ultrasound (US) of the penis is a second-level diagnostic test that specifically studies the haemodynamic pathophysiology of erectile function. Therefore, in clinical practice, it is usually applied in those conditions in which a potential vasculogenic aetiology of ED (e.g., diabetes mellitus, renal transplantation, multiple concomitant CV risk factors and/or overt peripheral vascular disease, and poor responders to oral therapy) is suspected. Peak systolic blood flow > 30 cm/s, end-diastolic velocity < 3 cm/s and resistance index > 0.8 are considered normal [419, 420]. Recent data suggest that duplex scanning as a haemodynamic study may be better at tailoring therapy for ED, such as for low-intensity shock wave treatment (LI-SWT) and for diagnosing vasculogenic ED [421]. Further vascular investigation is unnecessary if a duplex US examination is normal. 5.5.4 Arteriography and dynamic infusion cavernosometry or cavernosography Pudendal arteriography should be performed only in patients who are being considered for penile revascularisation [422]. Recent studies have advocated the use of computed tomography (CT) angiography as a diagnostic procedure prior to penile artery angioplasty for patients with ED and isolated penile artery stenosis [423]. Nowadays, dynamic infusion cavernosometry or cavernosography are infrequently used tools for diagnosing venogenic ED.

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5.5.5 Psychiatric and psychosocial assessment Whenever clinically indicated, patients with psychiatric disorders should be referred to a psychiatrist. In younger patients (< 40 years) with long-term primary ED [174], psychiatric assessment may be helpful before any clinical assessment is carried out. Mental health issues are frequently comorbid with ED. This is most evident for depression and anxiety related disorders, but may also include transitory states of altered mood (i.e., dysfunctional affective states resulting from a specific life stressor) [320, 424]. Relationship factors, including lack of satisfaction with the partner, poor sexual relationships, length of the relationship, or feeling emotionally disconnected from the partner during sex, have been related to erectile difficulties and dysfunction [424-426]. In contrast, feeling emotionally supported, and motivated toward intimacy are protective factors in men with ED [427]. Additionally, the cognitive factors underpinning organic and non-organic ED must also be assessed. Cognitive factors include male dysfunctional thinking styles and expectations about sexuality and sexual performance. These expectations result from the sexuality norms and stereotypes, shared by a given culture. Expectations emphasising high sexual performance in men, result in anxiety, which acts as a maintenance factor for ED [428]. Unrealistic expectations about male sexual performance may further align with internal causal attributions regarding the loss of erection (i.e., men attribute the loss of erection to themselves [sense of personal inadequacy]), thereby worsening ED [429]. Likewise, poor self-esteem and cognitive distraction from erotic cues, are expected to negatively affect ED [430, 431]. Psychosexual assessment in ED cases include a clinical interview considering all the previous topics. Clinicians are expected to collect information on the individual’s psychopathological symptoms, life stressors, relationship dynamics, cognitive style, and cognitive distraction sources [430]. Also, self-reported measures are frequently used within the psychological context. These may include measurement scales such as the Brief Symptom Inventory [432] for measuring psychopathology symptoms, the Sexual Dysfunctional Beliefs Questionnaire [433] or the Sexual Modes Questionnaire [434] for measuring dysfunctional cognitive styles in men. Figure 5: Psychiatric and psychosocial assessment

Collect evidence for specific life stressors

Evaluate psychosexual history and relaonship factors

Consider role of partner

Evaluate dysfunconal thinking style and expectaons regarding sexuality and erecle funcon

Consider cultural background

Decide on referral to (sexual) psychotherapy

Include psychosexual aspects as outcomes for treatment efficacy - relationship/intimacy - sexual satisfaction - well-being - flexible thinking style and expectations

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Table 12: Indications for specific diagnostic tests for ED Primary ED (not caused by acquired organic disease or psychogenic disorder). Young patients with a history of pelvic or perineal trauma, who could benefit from potentially curative revascularisation surgery or angioplasty. Patients with penile deformities that might require surgical correction (e.g., Peyronie’s disease and congenital penile curvature). Patients with complex psychiatric or psychosexual disorders. Patients with complex endocrine disorders. Specific tests may be indicated at the request of the patient or their partner. Medico-legal reasons (e.g., implantation of penile prosthesis to document end-stage ED, and sexual abuse). Table 13: Specific diagnostic tests for ED Nocturnal Penile Tumescence and Rigidity (NTPR) using Rigiscan® Vascular studies - Intracavernous vasoactive drug injection - Penile dynamic duplex ultrasonography - Penile dynamic infusion cavernosometry and cavernosography - Internal pudendal arteriography Specialised endocrinological studies Specialised psycho-diagnostic evaluation 5.5.6

Recommendations for diagnostic evaluation of ED

Recommendations Take a comprehensive medical and sexual history in every patient presenting with erectile dysfunction (ED). Consider psychosexual development, including life stressors, cultural aspects, and cognitive/thinking style of the patient regarding their sexual performance. Use a validated questionnaire related to ED to assess all sexual function domains (e.g., International Index of Erectile Function) and the effect of a specific treatment modality. Include a focused physical examination in the initial assessment of men with ED to identify underlying medical conditions and comorbid genital disorders that may be associated with ED. Assess routine laboratory tests, including glucose and lipid profile and total testosterone, to identify and treat any reversible risk factors and lifestyle factors that can be modified. Include specific diagnostic tests in the initial evaluation of ED in the presence of the conditions presented in Table 11.

5.6

Strength rating Strong

Strong Strong Strong Strong

Treatment of erectile dysfunction

5.6.1 Patient education - consultation and referrals Educational intervention is often the first approach to sexual complaints, and consists of informing patients about the psychological and physiological processes involved in the individual’s sexual response, in ways the patient can understand. This first level approach has been shown to favour sexual satisfaction in men with ED [435]. Accordingly, consultation with the patient should include a discussion of the expectations and needs of the patient’s and their sexual partner. It should also review the patient’s and partner’s understanding of ED and the results of diagnostic tests, and provide a rationale for treatment selection [436]. Patient and partner education is an essential part of ED management [436, 437], and may prevent misleading information that can be at the core of dysfunctional psychological processes underpinning ED. 5.6.2 Treatment options Based on the currently available evidence and the consensus of the Panel, a novel comprehensive therapeutic and decision-making algorithm (Figure 6) for treating ED, which takes into account the level of invasiveness of each therapy and its efficacy, has been presented. This newly-developed treatment algorithm was extensively discussed within the guidelines panel as an alternative to the traditional three-level concept, to better tailor a personalised therapy to individual patients, according to invasiveness, tolerability and effectiveness of the different therapeutic options and patients’ expectations. In this context, patients should be fully counselled with respect to all available treatment modalities.

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Erectile dysfunction may be associated with modifiable or reversible risk factors, including lifestyle or drugrelated factors [349]. These factors may be modified either before, or at the same time as, specific therapies are used. Likewise, ED may be associated with concomitant and underlying conditions (e.g., endocrine disorders and metabolic disorders such as diabetes, and some cardiovascular problems such as hypertension) which should always be well-controlled as the first step of any ED treatment [438]. Major clinical potential benefits of lifestyle changes may be achieved in men with specific co-morbid CV or metabolic disorders, such as diabetes or hypertension [349, 439]. As a rule, ED can be treated successfully with current treatment options, but it cannot be cured. The only exceptions are psychogenic ED, post-traumatic arteriogenic ED in young patients, and hormonal causes (e.g., hypogonadism) [53, 405], which potentially can be cured with specific treatments. Most men with ED are not treated with cause-specific therapeutic options. This results in a tailored treatment strategy that depends on invasiveness, efficacy, safety and cost, as well as patient preference [436]. In this context, physician-patient (partner, if available) dialogue is essential throughout the management of ED. Interesting insights come from a recent systematic review that showed a consistent discontinuation rate for all available treatment options (4.4.-76% for PDE5Is); 18.6-79.9% for intracavernous injections; 32-69.2% for urethral suppositories; and 30% for penile prostheses). Therapeutic ineffectiveness, adverse effects, quality of men’s intimate relationships and treatment costs are the most prevalent barriers to treatment utilisation [440].

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Figure 6: Management algorithm for erectile dysfunction Comprehensive medical and sexual history (assessing a detailed aetiological framework)

Before any therapeutic suggestions: Identify patient needs and expectations Shared decision-making Offer conjoint psycho-sexual and medical/physical treatment

Lifestyle changes and risk factor modifications

Identify and treat

“curable” causes of erectile dysfunction

Intracavernosal injection

Patients with definitive severe ED (Major non nervesparing pelvic , surgery neurogenic or traumatic causes)

Oral therapy with PDE5I

Vacuum device

Provide education and counselling to patient (and a partner, if available)

Topical/ Intraurethral Alprostadil

Assess therapeutic outcomes in terms of: • Patient self-percieved treatment invasiveness • Treatment-associated improvement of erectile function • Treatment-related side effects • Treatment-associated satisfaction

Vasculogenic ED only

LI-SWT (with/without PDE5I)

Inadequate treatment outcome

• • • • •

Assess adequate use of treatment options Provide new instructions and counselling Re-trial Treatment-associated satisfaction Consider treatment alternative or combined therapies

Inadequate treatment outcome

Penile prostheses implant

ED = erectile dysfunction; PDE5Is = phosphodiesterase type 5 inhibitors; LI-SWT = low-intensity shockwave therapy. 5.6.2.1 Oral pharmacotherapy Four potent selective PDE5Is have been approved by the European Medicines Agency (EMA) for treatment of ED [441]. Phosphodiesterase type 5 catalyses the hydrolysis of the second messenger cyclic guanosine monophosphate (cGMP) in the cavernous tissue; cGMP is involved in intra-cellular signalling pathways of cavernous smooth muscle. Accumulation of cGMP sets in motion a cascade of events at the intracellular level,

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which induces a loss of contractile tone of the penile vessels by lowering cytosolic Ca2+. Nitric oxide (NO) has an essential role in promoting the formation of cGMP and other pathways leading to corporeal smooth muscle relaxation and erection of the penis [438, 442]. This is associated with increased arterial blood flow, eventually leading to compression of the sub-tunical venous plexus followed by erection [443]. Since they are not initiators of erection, PDE5Is require sexual stimulation to facilitate an erection. Efficacy is defined as an erection, with rigidity, sufficient for satisfactory intercourse [438]. Sildenafil Sildenafil was launched in 1998 and was the first PDE5I available on the market [444]. It is administered in doses of 25, 50 and 100 mg. The recommended starting dose is 50 mg and should be adapted according to the patient’s response and adverse effects [444]. Sildenafil is effective 30-60 minutes after administration [444]. Its efficacy is reduced after a heavy, fatty meal due to delayed absorption. Efficacy may be maintained for up to 12 hours [445]. The pharmacokinetic profile for sildenafil is presented in Table 14. Adverse events (Table 15) are generally mild in nature and self-limited [446, 447]. After 24 weeks in a dose-response study, improved erections were reported by 56%, 77% and 84% in a general ED population taking 25, 50 and 100 mg sildenafil, respectively, compared to 25% of men taking placebo [448]. Sildenafil significantly improved patient scores for IIEF, sexual encounter profile question 2 (SEP2), SEP question 3 (SEP3) and General Assessment Questionnaire (GAQ) and treatment satisfaction. The efficacy of sildenafil in almost every subgroup of patients with ED has been successfully established, irrespective of age [449]. Recently, an orally disintegrating tablet (ODT) of sildenafil citrate at a dose of 50 mg has been developed, mainly for patients who have difficulty swallowing solid dosage forms. Tadalafil Tadalafil was licensed for treatment of ED in February 2003 and is effective from 30 minutes after administration, with peak efficacy after about 2 hours [450]. Efficacy is maintained for up to 36 hours [450] and is not affected by food [451]. Usually, tadalafil is administered in on-demand doses of 10 and 20 mg or a daily dose of 5 mg. The recommended on-demand starting dose is 10 mg and should be adapted according to the patient’s response and adverse effects [450, 452]. Pharmacokinetic data for tadalafil are presented in Table 14. Adverse effects (Table 15) are generally mild in nature and self-limited by continuous use. In pre-marketing studies, after 12 weeks of treatment in a dose-response study, improved erections were reported by 67% and 81% of men with ED taking 10 and 20 mg tadalafil, respectively, compared to 35% of men in the placebo control group [450]. Tadalafil significantly improves patient scores for IIEF, SEP2, SEP3, and GAQ and treatment satisfaction [450]. Efficacy of tadalafil has been confirmed in post-marketing studies [441, 453] and in almost every subgroup of patients with ED, including difficult-to-treat subgroups (e.g., diabetes mellitus) [454]. Tadalafil has also been shown to have a net clinical benefit in the short-term on ejaculatory and orgasmic functions in ED patients [455]. Daily tadalafil has been licensed for treatment of LUTS secondary to BPH. Therefore, it is useful in patients with concomitant ED and LUTS [456]. Recent data have confirmed that 40% of men aged > 45 years were combined responders for ED and LUTS/BPH to treatment with tadalafil 5 mg once daily, with symptom improvement after 12 weeks [457]. Vardenafil Vardenafil became commercially available in March 2003 and is effective from 30 minutes after administration [458], with one of three patients achieving satisfactory erections within 15 minutes of ingestion [459]. Its effect is reduced by a heavy, fatty meal. Doses of 5, 10 and 20 mg have been approved for on-demand treatment of ED. The recommended starting dose is 10 mg and should be adapted according to the patient’s response and adverse effects [460]. Pharmacokinetic data for vardenafil are presented in Table 14. Adverse events (Table 15) are generally mild in nature and self-limited by continuous use [460]. After 12 weeks in a dose-response study, improved erections were reported by 66%, 76% and 80% of men with ED taking 5, 10 and 20 mg vardenafil, respectively, compared with 30% of men taking placebo [460, 461]. Vardenafil significantly improved patient scores for IIEF, SEP2, SEP3, and GAQ and treatment satisfaction. Efficacy has been confirmed in post-marketing studies [460, 461]. The efficacy of vardenafil in almost every subgroup of patients with ED, including difficult-to-treat subgroups (e.g. diabetes mellitus), has been successfully established. An orodispersable tablet (ODT) formulation of vardenafil has been released [461]. Orodispersable tablet formulations offer improved convenience over film-coated formulations and may be preferred by patients. Absorption is unrelated to food intake and they exhibit better bio-availability compared to film-coated tablets [462]. The efficacy of vardenafil ODT has been demonstrated in several RCTs and did not seem to differ from the regular formulation [462-464].

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Avanafil Avanafil is a highly-selective PDE5I that became commercially available in 2013 [465]. Avanafil has a high ratio of inhibiting PDE5 as compared with other PDE subtypes, ideally allowing for the drug to be used for ED while minimising adverse effects (although head-to-head comparisons are not yet available) [466]. Doses of 50, 100 and 200 mg have been approved for on-demand treatment of ED [465]. The recommended starting dose is 100 mg taken as needed 15-30 minutes before sexual activity and the dose may be adapted according to efficacy and tolerability [465, 467, 468]. In the general population with ED, the mean percentage of attempts resulting in successful intercourse was approximately 47%, 58% and 59% for the 50, 100 and 200 mg groups, respectively, as compared with ~28% for placebo [465, 467]. Data from sexual attempts made within 15 minutes of treatment showed successful attempts in 64%, 67% and 71% of cases treated with avanafil 50, 100 and 200 mg, respectively. Dose adjustments are not warranted based on renal function, hepatic function, age or sex [467]. Pharmacokinetic data for avanafil are presented in Table 14 [465, 467]. Adverse effects are generally mild in nature (Table 15) [465, 467]. Pairwise meta-analytic data from available studies have suggested that avanafil significantly improved patient scores for IIEF, SEP2, SEP3 and GAQ, with an evident dose-response relationship [465, 469]. Administration with food may delay the onset of effect compared with administration in a fasting state but avanafil can be taken with or without food [470]. The efficacy of avanafil in many groups of patients with ED, including difficult-to-treat subgroups (e.g., diabetes mellitus), has been successfully established. As for dosing, 36.4% (28 of 77) of sexual attempts (SEP3) at < 15 minutes were successful with avanafil vs. 4.5% (2 of 44) after placebo (P < 0.01) [471]. A recent meta-analysis confirmed that avanafil had comparable efficacy with sildenafil, vardenafil and tadalafil [470]. Choice or preference among the different PDE5Is To date, no data are available from double- or triple-blind multicentre studies comparing the efficacy and/ or patient preference for the most-widely available PDE5Is (i.e., sildenafil, tadalafil, vardenafil, and avanafil). Choice of drug depends on frequency of intercourse (occasional use or regular therapy, 3-4 times weekly) and the patient’s personal experience. Patients need to know whether a drug is short- or long-acting, its possible disadvantages, and how to use it. A meta-analysis demonstrated that ED patients who prioritise high efficacy must use sildenafil 50 mg whereas those who optimise tolerability should initially use tadalafil 10 mg and switch to udenafil 100 mg if the treatment is not sufficient (however, udenafil 100 mg is not EMA or US Food and Drug Administration approved and is not available in Europe) [453]. The results of another clinical trial have revealed that tadalafil 5 mg once daily may improve erectile function among men who have a partial response to on-demand PDE5I therapy [472]. Continuous use of PDE5Is Animal studies have shown that chronic use of PDE5Is significantly improves or prevents the intracavernous structural alterations caused by age, diabetes or surgical damage [473-477]. No data exist in humans. In humans, it has been clinically demonstrated that treatment with tadalafil 5 mg once daily in men complaining of ED of various severities is well-tolerated and effective [478]. In 2007, tadalafil 2.5 and 5 mg/day were approved by the EMA for treatment of ED. According to the EMA, a once-daily regimen with tadalafil 2.5 or 5 mg might be considered suitable, based on patients’ choice and physicians’ judgement. In these patients, the recommended dose is 5 mg, taken once daily at approximately the same time. Overall, tadalafil, 5 mg once daily, provides an alternative to on-demand tadalafil for couples who prefer spontaneous rather than scheduled sexual activities or who anticipate frequent sexual activity, with the advantage that dosing and sexual activity no longer need to be linked. The appropriateness of the continuous use of a daily regimen should be re-assessed periodically [478, 479]. A recent integrated analysis has shown that no clinical populations of patients with ED seem to benefit overwhelmingly from tadalafil once daily over on-demand regimens and vice versa [480]. A recent RCT has shown that there is no clinically beneficial effect on endothelial dysfunction measured by flow-mediated dilation deriving from daily tadalafil when compared to placebo [481]. Although some authors have reported improved erectile function when long-term tadalafil 5 mg once daily is combined with sildenafil as needed [482], more safety analyses are required to give a formal recommendation on such a therapy.

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Table 14: S  ummary of the key pharmacokinetic data for the four PDE5Is currently EMA-approved to treat ED* Parameter Cmax Tmax (median) T1/2 AUC Protein binding Bioavailability

Sildenafil, 100 mg 0.8-1 hours 2.6-3.7 hours 1,685 μg.h/L 96% 41% 41%

Tadalafil, 20 mg 2 hours 17.5 hours 8,066 μg.h/L 94% NA NA

Vardenafil, 20 mg 0.9 hours 3.9 hours 56.8 μg.h/L 94% 15% 15%

Avanafil, 200mg 0.5-0.75 hours 6-17 hours 11.6 μg.h/L 99% 8-10% 8-10%

* Fasted state, higher recommended dose. Data adapted from EMA statements on product characteristics. Cmax = maximal concentration; Tmax = time-to-maximum plasma concentration; T1/2 = plasma elimination halftime; AUC = area under curve or serum concentration time curve. Table 15: Common adverse events of the four PDE5Is currently EMA-approved to treat ED* Adverse event Headache Flushing Dyspepsia Nasal congestion Dizziness Abnormal vision Back pain Myalgia

Sildenafil 12.8% 10.4% 4.6% 1.1% 1.2% 1.9%

Tadalafil 14.5% 4.1% 12.3% 4.3% 2.3% 6.5% 5.7%

Vardenafil 16% 12% 4% 10% 2% < 2%

Avanafil, 200mg 9.3% 3.7% uncommon 1.9% 0.6% None < 2% < 2%

* Adapted from EMA statements on product characteristics. Safety issues for PDE5Is (i) Cardiovascular safety Clinical trial results for the four PDE5Is and post-marketing data of sildenafil, tadalafil, and vardenafil have demonstrated no increase in myocardial infarction rates in patients receiving PDE5Is, as part of either RCTs or open-label studies, or compared to expected rates in age-matched male populations. None of the PDE5Is has an adverse effect on total exercise time or time-to-ischaemia during exercise testing in men with stable angina [441, 483]. Chronic or on-demand use is well-tolerated with a similar safety profile. The prescription of all PDE5Is in patients with CVD or in those with high CV risk should be based on the recommendations of the 3rd Princeton Consensus Panel [413]. (ii) Contraindication for the concomitant use of organic nitrates An absolute contraindication to PDE5Is is use of any form of organic nitrate (e.g., nitroglycerine, isosorbide mononitrate, and isosorbide dinitrate) or NO donors (e.g., other nitrate preparations used to treat angina, as well as amyl nitrite or amyl nitrate such as “poppers” that are used for recreation). They result in cGMP accumulation and unpredictable falls in blood pressure and symptoms of hypotension. The duration of interaction between organic nitrates and PDE5Is depends upon the PDE5I and nitrate used. If a PDE5I is taken and the patient develops chest pain, nitroglycerine must be withheld for at least 24 hours if sildenafil (and probably also vardenafil) is used (half-life, 4 hours), or at least 48 hours if tadalafil is used (half-life, 17.5 hours), and for no less than 12 hours if avanafil is used (half-life, 6-17 hours) [484-487]. (iii) Use caution with antihypertensive drugs Co-administration of PDE5Is with antihypertensive agents (e.g., angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, calcium blockers, β-blockers, and diuretics) may result in small additive decreases in blood pressure, which are usually minor [413]. In general, the adverse event profile of a PDE5I is not worsened by a background of antihypertensive medication, even when the patient is taking several antihypertensive agents [488]. (iv) Interaction with Nicorandil In vitro studies in animals suggest that the potassium channel opener nicorandil may potentiate the vasorelaxation induced by isoproterenol in isolated rat aorta by increasing cyclic GMP levels [489]. This may be due to the nitric oxide donating properties of nicorandil. Therefore, concurrent use of nicorandil and PDE5Is is also contraindicated. 58

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α-Blocker interactions All PDE5Is show some interaction with α-blockers. A recent meta-analysis concluded that a concomitant treatment with α-blockers and PDE5Is may produce changes in haemodynamic parameters, but it does not increase the rate of adverse events due to hypotension [490]. In everyday clinical practice, a patient presenting for ED should be stable on one medication before starting a PDE5Is, and the use of uroselective α-blockers is strongly preferred. Available historical data suggest that: • Sildenafil labelling advises that 50 or 100 mg sildenafil should be used with caution in patients taking an α-blocker (especially doxazosin). Hypotension is more likely to occur within 4 hours following treatment with an α-blocker. A starting dose of 25 mg is recommended [446]. • Concomitant treatment with vardenafil should only be initiated if the patient has been stabilised on their α-blocker therapy. Co-administration of vardenafil with tamsulosin is not associated with clinically significant hypotension [458, 460, 461]. • Tadalafil is not recommended in patients taking doxazosin, but this is not the case for tamsulosin [450, 491]. • Avanafil labelling currently reports that patients should be stable on α-blocker therapy prior to initiating avanafil. In these patients, avanafil should be initiated at the lowest dose of 50 mg. Conversely, in those patients already taking an optimised dose of avanafil, α-blocker therapy should be initiated at the lowest dose. Dosage adjustment Drugs that inhibit the CYP34A pathway inhibit the metabolic breakdown of PDE5Is, thus increasing PDE5Is blood levels (e.g., ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir and telithromycin). Therefore, lower doses of PDE5Is are necessary. However, other agents, such as rifampin, phenobarbital, phenytoin and carbamazepine, may induce CYP3A4 and enhance the breakdown of PDE5Is, so that higher doses of PDE5Is are required. Severe kidney or hepatic dysfunction may require dose adjustments or warnings. Management of non-responders to PDE5Is The two main reasons why patients fail to respond to a PDE5I are either incorrect drug use or lack of efficacy. Data suggest that an adequate trial involves at least six attempts with a particular drug [492]. The management of non-responders depends upon identifying the underlying cause [493]. Check that the medication has been properly prescribed and correctly used. The main reason why patients fail to use their medication correctly is inadequate counselling from their physician. The most common causes of incorrect drug use are: i) failure to use adequate sexual stimulation; ii) failure to use an adequate dose; and, iii) failure to wait an adequate amount of time between taking the medication and attempting sexual intercourse. Check that the patient has been using a licensed medication. There is a large counterfeit market in PDE5Is. The amount of active drug in these medications varies enormously and it is important to check how and from which source the patient has obtained his medication. PDE5I action is dependent on the release of NO by the parasympathetic nerve endings in the erectile tissue of the penis. The usual stimulus for NO release is sexual stimulation, and without adequate sexual stimulation (and NO release), the medication is ineffective. Furthermore, the reduced production of NO that occurs in diabetic patients due to peripheral neuropathy, is thought to be the justification for the higher failure rate of PDE5Is in this category of patients. Oral PDE5Is take different times to reach maximal plasma concentrations (Cmax) [445, 447, 462, 469, 494-496]. Although pharmacological activity is achieved at plasma levels below the maximal plasma concentration, there will be a period of time following oral ingestion of the medication during which the drug is ineffective. Even though all four drugs have an onset of action in some patients within 15-30 minutes of oral ingestion [447, 462, 494-496], most patients require a longer delay between taking the medication [460, 469, 497, 498]. Absorption of both sildenafil and vardenafil can be delayed by a heavy, fatty meal [499]. Absorption of tadalafil is less affected, and food has negligible effects on its bioavailability [494]. When avanafil is taken with a high-fat meal, the rate of absorption is reduced with a mean delay in Tmax of 1.25 hours and a mean reduction in Cmax of 39% (200 mg). There is no effect on the extent of exposure (area under the curve). The small changes in avanafil Cmax are considered to be of minimal clinical significance [465, 466, 469]. It is possible to wait too long after taking the medication before attempting sexual intercourse. The half-life of sildenafil and vardenafil is ~4 hours, suggesting that the normal window of efficacy is 6-8 hours following drug ingestion, although responses following this time period are recognised. The half-life of avanafil is 6-17 hours. Tadalafil has a longer half-life of ~17.5 hours, so the window of efficacy is longer at ~36 hours. Data

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from uncontrolled studies suggest patient education can help salvage an apparent non-responder to a PDE5I [493, 500-503]. After emphasising the importance of dose, timing, and sexual stimulation to the patient, erectile function can be effectively restored following re-administration of the relevant PDE5I [493, 500, 501]. A systematic review has addressed the association between genetic polymorphism, especially those encoding endothelial nitric oxide synthase, and the variability in response to PDE5Is [504]. Similar recent data have suggested that response to sildenafil treatment is also dependent on polymorphism in the PDE5A gene, which encodes the principal cGMP-catalysing enzyme in the penis, regulating cGMP clearance, and it is the primary target of sildenafil [505-507]. Clinical strategies in patients correctly using a PDE5Is Overall, treatment goals should be individualised to restore sexual satisfaction for patients and/or couples, and improve QoL based on patients’ expressed needs and desires [508]. In this context, data suggests that almost half of patients abandon first-generation PDE5Is within 1 year, with no single specific factor playing a major role in dropout rates [509]. Uncontrolled trials have demonstrated that hypogonadal patients not responding to PDE5Is may improve their response to PDE5Is after initiating testosterone therapy [53, 438, 510]. Therefore, in the real-life setting most patients with ED will first be prescribed a PDE5I, which is usually effective; however, if diagnostic criteria suggestive for testosterone deficiency are present, testosterone therapy may be more appropriate even in ED patients [5, 53]. Modification of other risk factors may also be beneficial, as previously discussed. Limited data suggest that some patients might respond better to one PDE5I than to another [511], and although these differences might be explained by variations in drug pharmacokinetics, they do raise the possibility that, despite an identical mode of action, switching to a different PDE5I might be helpful. However it is important to emphasise that the few randomised studies have shown any difference in clinical outcomes with different drugs and intake patterns in patients with classic ED [512] and in special populations such as people with diabetics [513]. In patients with severe ED, it has been suggested to combine tadalafil daily treatment with a shortacting PDE5I (such as sildenafil), without any significant increase in adverse effects [482]. Robust prospective data from RCTs to support combination treatments with any oral preparations are still lacking and should therefore be used with caution. If drug treatment fails, then patients can be offered an alternative therapy such as intracavernous injection therapy or use of a vacuum erection device (VED). Likewise, limited data suggest combination of a PDE5I with as intracavernous, intraurethral or topical alprostadil in patients who have previously failed therapy with either drug [514]. Review findings have indicated that, with all three formulations, combination therapy results in improved outcome compared with any of the drugs as monotherapy, even for patients with post-prostatectomy ED. Treatment-emergent adverse events of the combined treatment do not result in treatment discontinuation [514]. 5.6.2.2 Topical/Intraurethral alprostadil The vasoactive agent alprostadil can be administered intraurethrally with two different formulations. The first delivery method is topical, using a cream that includes a permeation enhancer to facilitate absorption of alprostadil (200 and 300 μg) via the urethral meatus [515, 516]. Clinical data are still limited. Significant improvement compared to placebo was recorded for IIEF-EF domain score, SEP2 and SEP3 in a broad range of patients with mild-to-severe ED [517]. Adverse effects include penile erythema, penile burning, and pain that usually resolve within 2 hours of application. Systemic adverse effects are rare. Topical alprostadil (VITAROS™) at a dose of 300 μg is available in some European countries. Recently, a randomised cross-over clinical trial has shown that, compared to the standard administration route, direct delivery within the urethral meatus can increase efficacy and confidence among patients, without increasing adverse effects [518]. The second delivery method is by intra-urethral insertion of a specific formulation of alprostadil (125-1000 μg) in a medicated pellet (MUSE™) [229]. Erections sufficient for intercourse are achieved in 30-65.9% of patients. In clinical practice, it is recommended that intra-urethral alprostadil is initiated at a dose of 500 μg, as it has a higher efficacy than the 250 μg dose, with minimal differences with regard to adverse events. In case of unsatisfactory clinical response, the dose can be increased to 1000 μg [519-521]. The application of a constriction ring at the root of the penis may improve efficacy [520, 521]. Overall, the most common adverse events are local pain (29-41%) and dizziness with possible hypotension (1.9-14%). Penile fibrosis and priapism are rare (< 1%). Urethral bleeding (5%) and urinary tract infections (0.2%) are adverse events related to the mode of administration. Efficacy rates are significantly lower than for intracavernous pharmacotherapy [522], with ~30% adherence to long-term therapy. Intraurethral pharmacotherapy provides an alternative to intracavernous injections in patients who prefer a less-invasive, although less-efficacious treatment. 60

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5.6.2.3 Shockwave therapy The use of LI-SWT has been increasingly proposed as a treatment for vasculogenic ED over the last decade, being the only currently marketed treatment that might offer a cure, which is the most desired outcome for most men suffering from ED [421, 523-530]. Overall, several single-arm trials have shown a beneficial effect of LI-SWT on patient-reported erectile function, but data from prospective randomised trials are conflicting, and many questions remain to be answered especially because of the heterogeneity among shockwave generators (i.e., electrohydraulic, electromagnetic, piezoelectric and electropneumatic); type of shockwaves delivered (i.e., focused, linear, semi-focused and unfocused); set-up parameters (e.g., energy flux density and number of pulses per session) and treatment protocols (i.e.,duration of treatment, number of sessions per week, total number of shockwave pulses delivered and penile sites of application) [531]. Most of the studies have suggested that LI-SWT can significantly increase the IIEF and EHS in patients with mild vasculogenic ED, although this improvement appears modest. Few studies have shown an improvement in penile haemodynamic parameters after LI-SWT, but the clinical meaning of this improvement remains unclear [531, 532]. Likewise, data suggest that LI-SWT could ameliorate erection quality even in patients with severe ED who are either PDE5Is non-responders [528, 533, 534] or inadequate responders [535], thus reducing the immediate need for more invasive treatments. However, larger prospective RCTs and longer-term follow-up data are necessary to provide clinicians with more confidence regarding the use and effectiveness of LI-SWT for ED. Further clarity is also needed in defining treatment protocols that can result in greater clinical benefits [536, 537]. As a whole, according to the available data and the novel treatment decision algorithm, LI-SWT may be offered to patients with vasculogenic ED, although they should be fully counselled before treatment. 5.6.2.4 Psychosexual counselling and therapy For patients with a recognised psychological problem [538], psychosexual therapy may be given either alone or with another therapeutic approach to improve couples’ sexual satisfaction and partners’ sexual function [539]. Psychosexual therapy requires ongoing follow-up and has had variable results [540]. Despite this psychological treatment including different modalities (e.g., sexual skills training, marital therapy and psychosexual education) [435], Cognitive and Behavioural Therapy (CBT), including group or couple format, is recommended [430]. Cognitive and behaviour therapy is aimed at altering dysfunctional cognitive and behavioural patterns influencing ED, and increasing adjustment during the course of the disorder. Some of its techniques include identifying triggers preceding erectile difficulties, cognitive restructuring of dysfunctional thinking styles, learning coping skills aimed at dealing with erectile difficulties and emotional symptoms, and relapse prevention. The CBT approach combined with medical treatment for ED has received empirical support and is considered an optimal procedure [430]. Moreover, there is preliminary evidence supporting the role of mindfulness-based therapy for ED and associated outcomes such as sexual satisfaction [541]. 5.6.2.5 Hormonal treatment The advice of an endocrinologist should be sought for managing patients with certain hormonal abnormalities or endocrinopathies [405]. Testosterone deficiency is either a result of primary testicular failure or secondary to pituitary/hypothalamic causes (e.g., a functional pituitary tumour resulting in hyperprolactinaemia) [405, 542]. When clinically indicated [543], testosterone therapy (intramuscular, transdermal, or oral) can be considered for men with low or low-normal testosterone levels and concomitant problems with their sexual desire, erectile function and dissatisfaction derived from intercourse and overall sex life (see Section 3.6 for a comprehensive discussion of testosterone therapy). 5.6.2.6 Vacuum erection devises Vacuum erection devices (VED) provide passive engorgement of the corpus cavernosum, together with a constrictor ring placed at the base of the penis to retain blood within the corpus. Published data report that efficacy, in terms of erections satisfactory for intercourse, is as high as 90%, regardless of the cause of ED and satisfaction rates range between 27% and 94% [544, 545]. Most men who discontinue use of VEDs do so within 3 months. Long-term use of VEDs decreases to 50-64% after 2 years [546]. The most common adverse events include pain, inability to ejaculate, petechiae, bruising, and numbness [545]. Serious adverse events (skin necrosis) can be avoided if patients remove the constriction ring within 30 minutes. Vacuum erection devices are contraindicated in patients with bleeding disorders or on anticoagulant therapy [547, 548]. Vacuum erection devices may be the treatment of choice in well-informed older patients with infrequent sexual intercourse and co-morbidity requiring non-invasive, drug-free management of ED [544, 545, 549]. 5.6.2.7 Intracavernous injections therapy Intracavernous administration of vasoactive drugs was the first medical treatment introduced for ED [503, 550]. According to invasiveness, tolerability, effectiveness and patients’ expectations (Figure 6), patients may be offered intracavernous injections. The success rate is high (85%) [522, 551]. SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021

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5.6.2.7.1 Alprostadil Alprostadil (CaverjectTM, Edex/ViridalTM) was the first and only drug approved for intracavernous treatment of ED [503, 552]. Intracavernous alprostadil is most efficacious as a monotherapy at a dose of 5-40 μg (40 μg may be offered off label in some European countries). The erection appears after 5-15 minutes and lasts according to the dose injected, but with significant heterogeneity among patients. An office-training programme is required for patients to learn the injection technique. In men with limited manual dexterity, the technique may be taught to their partners. The use of an automatic pen that avoids a view of the needle may be useful to resolve fear of penile puncture and simplifies the technique. Efficacy rates for intracavernous alprostadil of > 70% have been found in the general ED population, as well as in patient subgroups (e.g., men with diabetes or CVD), with reported satisfaction rates of 87-93.5% in patients and 86-90.3% in partners after the injections [503, 550]. Complications of intracavernous alprostadil include penile pain (50% of patients reported pain only after 11% of total injections), excessively-prolonged undesired erections (5%), priapism (1%), and fibrosis (2%) [503, 550, 553]. Pain is usually self-limited after prolonged use and it can be alleviated with the addition of sodium bicarbonate or local anaesthesia [503, 550, 554]. Cavernosal fibrosis (from a small haematoma) usually clears within a few months after temporary discontinuation of the injection programme. However, tunical fibrosis suggests early onset of Peyronie’s disease and may indicate stopping intracavernous injections indefinitely. Systemic adverse effects are uncommon. The most common is mild hypotension, especially when using higher doses. Contraindications include men with a history of hypersensitivity to alprostadil, men at risk of priapism, and men with bleeding disorders. Despite these favourable data, drop-out rates of 41-68% have been reported for intracavernous pharmacotherapy [503, 550, 555, 556], with most drop-outs occurring within the first 2-3 three months. In a comparative study, alprostadil monotherapy had the lowest discontinuation rate (27.5%) compared to overall drug combinations (37.6%), with an attrition rate after the first few months of therapy of 10% per year [557]. Reasons for discontinuation included desire for a permanent mode of therapy (29%), lack of a suitable partner (26%), poor response (23%) (especially among early drop-out patients), fear of needles (23%), fear of complications (22%), and lack of spontaneity (21%). Careful counselling of patients during the office-training phase as well as close follow-up are important in addressing patient withdrawal from an intracavernous injection programme [558-560]. 5.6.2.8 Combination therapy Table 16 details the available intracavernous injection therapies (compounds and characteristics). Combination therapy enables a patient to take advantage of the different modes of action of the drugs being used, as well as alleviating adverse effects by using lower doses of each drug. • Papaverine (20-80 mg) was the first oral drug used for intracavernous injections. It is most commonly used in combination therapy because of its high incidence of adverse effects as monotherapy. Papaverine is currently not licensed for treatment of ED. • Phentolamine has been used in combination therapy to increase efficacy. As monotherapy, it produces a poor erectile response. • Sparse data in the literature support the use of other drugs, such as vasoactive intestinal peptide (VIP), NO donors (linsidomine), forskolin, potassium channel openers, moxisylyte or calcitonin gene-related peptide, usually combined with the main drugs [561, 562]. Most combinations are not standardised and some drugs have limited availability worldwide. • Bimix, Trimix: papaverine (7.5-45 mg) plus phentolamine (0.25-1.5 mg) (also known as Bimix), and papaverine (8-16 mg) plus phentolamine (0.2-0.4 mg) plus alprostadil (10-20 μg) (also known as Trimix), have been widely used with improved efficacy rates, although they have never been licensed for ED [563, 564]. Trimix has the highest efficacy rates, reaching 92%; this combination has similar adverse effects as alprostadil monotherapy, but a lower incidence of penile pain due to lower doses of alprostadil. However, fibrosis is more common (5-10%) when papaverine is used (depending on total dose). • InvicorpTM: Vasoactive intestinal peptide (25 μg) plus phentolamine mesylate (1-2 mg Invicorp), currently licensed in Scandinavia, is a combination of two active components with complementary modes of action. Clinical studies have shown that the combination is effective for intracavernous injections in > 80% of men with ED, including those who have failed to respond to other therapies and, unlike existing intracavernous therapies, is associated with a low incidence of penile pain and a virtually negligible risk of priapism [565]. Despite high efficacy rates, 5-10% of patients do not respond to combination intracavernous injections. The combination of sildenafil with intracavernous injection of the triple combination regimen may salvage as many as 31% of patients who do not respond to the triple combination alone [566]. However, combination therapy is associated with an increased incidence of adverse effects in 33% of patients, including dizziness in 20% of patients. This strategy can be considered in carefully selected patients before proceeding to a penile implant.

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Table 16: Intracavernous injection therapy - compounds and characteristics Name Caverject™ or Edex/Viridal™ Papaverine

Substance Alprostadil

Dosage 5-40 µg/mL

Efficacy ~ 70%

Papaverine

20 - 80 mg

< 55%

Phentolamine

Phentolamine

0.5 mg/mL

Poor efficacy as monotherapy

Bimix

Papaverine + Phentolamine

30 mg/mL + 0.5 mg/mL

~ 90%

Trimix

Papaverine + Phentolamine + Alprostadil Vasoactive intestinal peptide (VIP) + Phentolamine

30 mg/mL + 1 mg/mL + 10 µg/mL 25 µg + 1-2 mg

~ 92%

Invicorp™

~ 80%

Adverse Events Penile pain, priapism, fibrosis Elevation of liver enzymes, priapism, fibrosis Systemic hypotension, reflex tachycardia, nasal congestion, and gastrointestinal upset Similar to Alprostadil (less pain) Similar as Alprostadil (less pain) Similar as Alprostadil without pain

Comment Easily available Abandoned as monotherapy Abandoned as monotherapy

Not licensed for the treatment of ED Not licensed for the treatment of ED Easily available

There are currently several potential novel treatment modalities for ED, from innovative vasoactive agents and trophic factors to stem cell therapy and gene therapy. Most of these therapeutic approaches require further investigation in large-scale, blinded, placebo-controlled randomised studies to achieve adequate evidencebased and clinically-reliable recommendation grades [567-572]. A recent systematic review has concluded that five completed human clinical trials have shown promise for stem cell therapy as a restorative treatment for ED [573]. 5.6.2.8.1 Erectile dysfunction after radical prostatectomy Use of pro-erectile drugs following RP is important in achieving post-operative erectile function and to allow patients to resume sexual activity. There is also some evidence in animal studies that this may avoid cavernous fibrosis and maintain penile length. Several trials have shown improvements in erectile function after RP in patients receiving drugs (any therapeutic or prophylactic) for ED. Early compared with delayed erectile function treatment affects the natural recovery time for potency [574], although there is a lack of data to support any specific regimen, which is either optimal for penile rehabilitation or may result in the achievement of spontaneous, non-pharmacologically assisted erections [363, 575, 576]. In prospective studies, there has been no evidence that penile rehabilitation itself increases the chances of spontaneous recovery of erectile function in men following nerve-sparing RP (NSRP) [576]. The currently available therapeutic armamentarium follows the treatment algorithm for ED, which is shown in Figure 4. Management of post-RP ED has been revolutionised by the advent of PDE5Is, with their demonstrated efficacy, ease of use, good tolerability, excellent safety, and positive impact on QoL. In this context, it must be emphasised that post-RP, ED patients are poor responders to PDE5Is. Since their launch on the market, PDE5Is have been considered as the first-line therapy in patients who have undergone NS surgery, regardless of the surgical technique used [363, 374, 375]. Several clinical parameters have been identified as potential predictors of PDE5Is outcomes in men undergoing RP. Patient age, baseline erectile function, and quality of NS technique are key factors in preserving post-RP erectile function [374, 375, 383, 577]. The response rate to sildenafil treatment for ED after RP in different trials has ranged from 35% to 75% among those who underwent NSRP and from 0% to 15% among those who underwent non-NSRP [374, 578]. Early use of high-dose sildenafil after RP is associated with preservation of smooth muscle within the corpus cavernosum [579]. A single study demonstrated that daily sildenafil also results in a greater return of spontaneous normal erectile function after RP compared to placebo following bilateral NSRP in patients who were fully potent before surgery [580]. Conversely, a more recent prospective, randomised, placebo-controlled study, which assessed the effects of nightly sildenafil citrate therapy during penile rehabilitation using nocturnal

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penile rigidity score in addition to the IIEF-EF domain showed no therapeutic benefit for nightly sildenafil when compared to on-demand dosing in recovery of erectile function post-prostatectomy [581]. A large multicentre trial in Europe and the USA investigated the effects of tadalafil in patients with ED following bilateral NSRP. Erectile function was improved in 71% of patients treated with 20 mg tadalafil versus 24% of those treated with placebo, while the rate of successful intercourse attempts was 52% with 20 mg tadalafil versus 26% with placebo [582]. Moreover, a randomised, double-blind, double-placebo trial in men < 68 years of age and with normal pre-operative erectile function who underwent NSRP at 50 centres from nine European countries and Canada, compared tadalafil once daily with placebo [576]. Tadalafil was most effective for drugassisted erectile function in men with ED following NSRP and data suggested a potential role for tadalafil once daily (provided early after surgery) in contributing to the recovery of post-operative erectile function and maintaining penile length [576]. Conversely, unassisted or spontaneous recovery of erectile function was not improved after cessation of active therapy for 9 months [576]. However, tadalafil once daily improved QoL post-operatively, both at double-blind and open label treatment periods [583]. Similarly, vardenafil has been tested in patients with ED following NSRP in a randomised, multicentre, prospective, placebo-controlled study [584]. Following bilateral NSRP, erectile function improved by 71% and 60% with 10 and 20 mg vardenafil, respectively. An extended analysis of the same cohort of patients showed the benefit of vardenafil compared to placebo in terms of intercourse satisfaction, hardness of erection, orgasmic function, and overall satisfaction with sexual experience [585]. A randomised, double-blind, doubledummy, multicentre, parallel-group study in 87 centres across Europe, Canada, South Africa and the USA, compared on-demand and nightly dosing of vardenafil in men with ED following bilateral NSRP [575]. In patients whose pre-operative erectile function domain score was > 26, vardenafil was efficacious when used on demand [575]. A double-blind, placebo-controlled, parallel-group study in 298 patients with ED after bilateral NSRP randomised to 100 or 200 mg avanafil or placebo (30 minutes before sexual activity) for 12 weeks showed significantly greater increases in SEP2 and SEP3 as well as in mean change of IIEF erectile function domain score with 100 and 200 mg avanafil versus placebo (P < 0.01) [415]. A recent Cochrane database systematic review analysed data from eight RCTs [586]. It showed that scheduled PDE5I may have little or no effect on short-term (up to 12 months) self-reported potency when compared to placebo or no treatment. In this study, daily PDE5I made little to no difference in short- and long-term erectile function. The authors conclude that penile rehabilitation strategies using PDE5I following RP do not increase self-reported potency and erectile function compared to on-demand use. Therefore, daily PDE5Is result in little to no difference in both short- and long-term (> 12 months) self-reported potency when compared to scheduled use. Finally, at short-term follow-up, daily PDE5I may result in little or no effect on self-reported potency when compared to scheduled intra-urethral application of prostaglandin E1. Historically, the treatment options for post-RP ED have included intracavernous injections [587], urethral microsuppository [374, 588], VED [363, 374, 589, 590], and penile implants [374, 591, 592]. Intracavernous injections and penile implants had been suggested as second- and third-line treatments, respectively, when oral PDE5Is are not adequately effective or not suitable for post-operative patients [362, 363, 593]. A recent meta-analysis has shown that the early use of VED has an excellent therapeutic effect on post-RP patients and no serious adverse effects, therefore it should be considered as a therapeutic alternative to discuss with the patient [594]. A recent systematic review has suggested that pelvic floor muscle training combined with bio-feedback is a promising alternative to pharmacological treatments, although there is a need for future well-powered, rigorously designed RCTs to draw strong conclusions [595]. 5.6.2.9 Vascular surgery 5.6.2.9.1 Surgery for post-traumatic arteriogenic ED In young patients with pelvic or perineal trauma, surgical penile revascularisation has a 60-70% long-term success rate [548, 596]. The stenosis must be confirmed by penile pharmaco-arteriography. Corporeal venoocclusive dysfunction is a contraindication to revascularisation and must be excluded by dynamic infusion cavernosometry or cavernosography. 5.6.2.9.2 Venous ligation surgery Venous ligation surgery for veno-occlusive dysfunction is no longer recommended because of poor long-term results [596].

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5.6.2.9.3 Penile prostheses The surgical implantation of a penile prosthesis may be considered in patients who (i) are not suitable for different pharmacotherapies or prefer a definitive therapy; and, (ii) do not respond to pharmacological therapies (Figure 6) [597]. A systematic review addressing cause and duration of symptoms before implantation has shown that most men receiving a penile prosthesis have an organic cause of ED, with vascular disease, diabetes, and previous pelvic surgery/trauma being the most common [598]. Similar findings have been reported by a prospective registry of penile prostheses with > a 3-year collection period in the UK; the three commonest aetiological factors for ED were diabetes, prostate surgery and Peyronie’s disease [599]. The mean duration of ED symptoms before surgical intervention ranges from 3-6 six years [598]. The two currently available classes of penile implants include inflatable (two- and three-piece) and semi-rigid devices (malleable, mechanical and soft flexible) [374, 591, 600-602]. Patients may prefer the three-piece inflatable devices due to the more “natural” erections obtained, although no prospective RCTs have compared satisfaction rates with both types of implants. The two-piece inflatable prosthesis can be a viable option among patients who are deemed at high-risk of complications with reservoir placements (e.g., previous abdominal surgery). Semi-rigid prostheses result in a firm penis, which may be manually placed in an erect or flaccid state and offer the advantage of a simple implant technique, as well as easy use for the patient [374, 591, 600, 601]. Conversely, they can have the disadvantage of unnatural persistent erection and reduced concealability [601, 603]. They may also be an option in men with limited manual dexterity. There are two main surgical approaches for penile prosthesis implantation: peno-scrotal and infrapubic [600, 601, 603, 604]. The peno-scrotal approach has been suggested to provide an excellent exposure; afford proximal crural exposure, avoid dorsal nerve injury, and permit direct visualisation of pump placement. However, with this approach, the reservoir is either placed blindly into the retropubic space, which can result in visceral injury in patients with a history of major pelvic surgery (mainly radical cystectomy) or a separate incision in the abdomen is placed under direct vision. A recent systematic review comparing the satisfaction and complication rates of the different surgical approaches has shown that there is no specific advantage between the two, but rather it is recommended that surgeons have knowledge of both techniques and are capable of tailoring the incision strategy for complex cases [605]. Revision surgery is associated with poorer outcomes and may be more challenging. Regardless of the indication, prosthesis implantation has one of the highest satisfaction rates (92-100% in patients and 91-95% in partners) among the treatment options for ED with appropriate counselling [374, 591, 600, 606-614]. In patients with favourable oncological prognosis after RP for PCa, a contemporary surgery to treat both ED, with the implant of a penile prosthesis, and stress urinary incontinence (male sling or artificial urinary sphincter) is effective and durable and has an established and definitive role to address both problems [374, 591, 615-617]. Structured psychosexual counselling may improve sexuality and sexual well-being in both patients and their partners after penile implant surgery [618]. 5.6.2.9.4 Penile prostheses implantation: complications Historically, the two main complications of penile prosthesis implantation are mechanical failure and infection. Several technical modifications of the most commonly used three-piece prostheses (e.g., AMS 700CX/CXRTM and Titan Zero degreeTM) resulted in mechanical failure rates of < 5% after 5 years of follow-up [591, 619, 620]. Careful surgical techniques with appropriate antibiotic prophylaxis against Gram-positive and Gram-negative bacteria reduced infection rates to 2-3% with primary implantation in low-risk patients and in high-volume centres, although the definition of a high-volume centre still needs clarification [621-624]. The infection rate may be further reduced to 1-2% by implanting an antibiotic-impregnated prosthesis (AMS Inhibizone™) or hydrophilic-coated prosthesis (Coloplast Titan™) [591, 621, 625-628]. Methods that decrease infections include using coated prostheses and strictly adhering to surgical techniques that avoid prolonged wound exposure and skin contact minimisation (i.e., no-touch technique). Techniques that might prevent penile prostheses infection but lack definitive evidence include the use of prolonged post-operative antibiotics (> 24 hours), shaving with clippers, and preparation with chlorhexidinealcohol [629, 630]. Identification and pre-treatment of patients who are colonised with nasal Staphylococcus aureus with mupirocin and chlorhexidine prior to surgery has been shown to reduce the incidence of postoperative surgical site infection from 4.4% to 0.9% in a placebo-controlled randomised trial [631]. On the whole, growing evidence suggests that the risk of penile prosthesis infection has reduced over the last few decades with device improvement and surgical expertise [632]. Higher-risk populations include patients undergoing revision surgery, those with impaired host defences (immunosuppression, diabetes mellitus, or spinal cord injury) or those with penile corporal fibrosis [591, 600, 622, 633-635]. A recent large database-study has shown that diabetes mellitus is a risk factor for penile

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prostheses infection, highlighting the need for optimal patient selection other than raising the question of whether lowering this risk by optimising glycaemic control before surgery [636]. Unfortunately, there are no RCTs determining the ideal and/or correct threshold of glycated haemoglobin that is acceptable prior to implant surgery in diabetic patients [637]. Recently, a large-cohort, multicentre, retrospective analysis in men with diabetes who received a Coloplast Titan™ implant demonstrated that vancomycin + gentamicin was the most efficacious combination of antibiotics used for implants dipping in terms of preventing postoperative infection and subsequent explantation and revision [638, 639]. Infection requires removal of the prosthesis and antibiotic administration. Alternatively, removal of the infected device with immediate replacement with a new prosthesis has been described using a wash-out protocol with successful salvages achieved in > 80% of cases [622, 634, 640, 641]. A final recommendation on how to proceed after removal in this setting cannot be given. The majority of revisions are secondary to mechanical failure and combined erosion or infection [627, 629]. Ninety-three percent of cases are successfully revised, providing functioning penile prosthesis [621, 622, 640, 642, 643]. Besides infection and mechanical failure, impending erosion involving the distal lateral corpora, urethra, glans or other structures can occur in 1-6% of cases after surgery [644]. Similarly glans ischaemia and necrosis have been reported in about 1.5% of patients [644, 645]. Risk factors for these serious complications are higher in those patients with significant vascular impairment, such as patients with diabetes, or who have undergone concomitant lengthening procedures. 5.6.2.9.4.1 Conclusions about penile prostheses implantation Penile implants are an effective solution, usually for patients who do not respond to more conservative therapies. There is sufficient evidence to recommend this approach in patients not responding to less-invasive treatments due to its high efficacy, safety and satisfaction rate [646]. There are also currently no head to head studies comparing the different manufacturers’ implants, demonstrating superiority of one implant type over another [647]. Table 17: Penile prostheses models available on the market Semi-rigid prostheses AMS Tactra™ [Boston Scientific] Genesis™ [Coloplast]

Tube™ [Promedon] ZSI 100™ [Zephyr] Virilis II™ [Subrini]

5.6.3

Inflatable prostheses Two-piece Three-piece AMS Ambicor™ [Boston Scientific] Titan™ [Coloplast] Titan OTR NB™ (Narrow base) [Coloplast] Titan Zero Degree™ AMS 700 CX™ [Boston Scientific] AMS 700 LGX™ [Boston Scientific] AMS 700 CXR™ [Boston Scientific] ZSI 475™ [Zephyr]

Recommendations for treatment of ED

Recommendations Assess all patients for inadequate/incorrect information about the mechanism of action and the ways in which drugs should be taken, as they are the main causes of a lack of response to phosphodiesterase type 5 inhibitors (PDE5Is). Use Cognitive Behaviour Therapy as a psychological approach (include the partner) combined with medical treatment to maximise treatment outcomes. Discuss with patients undergoing radical prostatectomy (any technique) about the risk of sexual changes other than erectile dysfunction (ED), including libido reduction, changes in orgasm, anejaculation, Peyronie’s like disease and penile size changes. Initiate lifestyle changes and risk factor modification prior to, or at the same time, as initiating ED treatments. Treat a curable cause of ED first, when found. Use PDE5Is as first-line therapeutic option. Use topical/intraurethral alprostadil as an alternative first-line therapy in well-informed patients who do not wish or are not suitable for oral vasoactive therapy.

66

Strength rating Weak

Strong Strong

Strong Weak Strong Weak

SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021

Use topical/intraurethral alprostadil as an alternative first-line therapy, in well-informed patients, who do not wish to have intracavernous injections or in patients who prefer a lessinvasive therapy. Use low intensity shockwave treatment (LI-SWT) in patients with mild vasculogenic ED or as an alternative first-line therapy in well-informed patients who do not wish or are not suitable for oral vasoactive therapy or desire a curable option. Use LI-SWT in vasculogenic ED patients who are poor responders to PDE5Is. Use vacuum erection devices (VEDs) as first-line therapy in well-informed patients with infrequent sexual intercourse and co-morbidity requiring non-invasive, drug-free management of ED. Use intracavernous injections as an alternative first-line therapy in well-informed patients or as second-line therapy. Use implantation of a penile prosthesis if other treatments fail or based upon patient preference. Data is inadequate to support the use of any specific regimen for penile rehabilitation after radical prostatectomy. Pro-erectile treatments should start at the earliest opportunity after radical prostatectomy/ pelvic surgery and other curative treatments for prostate cancer.

Weak

Weak

Weak

Strong Strong Strong Weak

5.6.4 Follow-up Follow-up is important in order to assess efficacy and safety of the treatment provided. It is also essential to assess patient satisfaction since successful treatment for ED goes beyond efficacy and safety. Physicians must be aware that there is no single treatment that fits all patients or all situations as described in detail in the previous section.

6.

DISORDERS OF EJACULATION

6.1

Introduction

Ejaculation is a complex physiological process that comprises emission and expulsion processes and is mediated by interwoven neurological and hormonal pathways [648]. Any interference with those pathways may cause a wide range of ejaculatory disorders (Table 18). Table 18: Spectrum of ejaculation disorders Premature ejaculation Retarded or delayed ejaculation Anejaculation Painful ejaculation Retrograde ejaculation Anorgasmia Haemospermia

6.2

Premature ejaculation

6.2.1 Epidemiology Historically, the main problem in assessing the prevalence of PE has been the lack of a universally recognised definition at the time that surveys were conducted [176]. See Section 4.2 for a comprehensive discussion about epidemiology of PE. 6.2.2 Pathophysiology and risk factors The aetiology of PE is unknown, with few data to support suggested biological and psychological hypotheses, including anxiety [649-653], penile hypersensitivity [654-660] and 5-hydroxytryptamine (HT) receptor dysfunction [661-666]. The classification of PE into four subtypes [185] has contributed to a better delineation of lifelong, acquired, variable and subjective PE [667-669]. It has been hypothesised that the pathophysiology of lifelong PE is mediated by a complex interplay of central and peripheral serotonergic, dopaminergic, oxytocinergic, endocrinological, genetic and epigenetic factors [670]. Acquired PE may occur due to psychological problems - such as sexual performance anxiety, and psychological or relationship problems and/or co-morbidity, including ED, prostatitis and hyperthyroidism [671-673]. SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021

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A significant proportion of men with ED also experience PE [193, 345]. High levels of performance anxiety related to ED may worsen PE, with a risk of misdiagnosing PE instead of the underlying ED. According to the National Health and Social Life Survey (NHSLS), the prevalence of PE is not affected by age [181], unlike ED, which increases with age. Conversely, other data depicted an increased prevalence with ageing [653]; for instance, Verze et al. reported that PE prevalence based on the Premature Ejaculation Diagnostic Tool (PEDT) score (> 11) [674] proportionally increased with age [675]. Similarly, in a recent systematic review, PE was found to be more common in older age, with peak prevalence in men aged 60-69 years [676]. Premature ejaculation is not affected by marital or income status [181, 675]. However, PE is more common in Black men, Hispanic men, and men from regions where an Islamic background is common [180, 677] and prevalence may be higher in men with a lower educational level [181, 193]. Other risk factors include genetic predisposition [666, 678-681], poor overall health status and obesity [181], prostate inflammation [331, 682-685], hyperthyroidism [671], low prolactin levels [686], high testosterone levels [687], vitamin D and B12 deficiency [688, 689], diabetes [690, 691], MetS [692, 693], lack of physical activity [694], emotional problems and stress [181, 695, 696], depressive symptoms [696], and traumatic sexual experiences [181, 193]. In the only published study on risk modification/ prevention strategies [697], successful eradication of causative organisms in patients with chronic prostatitis and PE produced marked improvements in intravaginal ejaculatory latency time (IELT) and ejaculatory control compared to untreated patients. 6.2.3 Impact of PE on quality of life Men with PE are more likely to report low satisfaction with their sexual relationship, low satisfaction with sexual intercourse, difficulty relaxing during intercourse, and less-frequent intercourse [269, 698, 699]. However, the negative impact of PE extends beyond sexual dysfunction. Premature ejaculation can have a detrimental effect on self-confidence and the relationship with the partner, and may sometimes cause mental distress, anxiety, embarrassment and depression [269, 700, 701]. Moreover, PE may also affect the partner’s sexual functioning and their satisfaction with the sexual relationship decreases with increasing severity of the patient’s condition [702-704]. Despite the possible serious psychological and QoL consequences of PE, few men seek treatment. In the Global Study of Sexual Attitudes and Behaviors survey, 78% of men who self-reported a sexual dysfunction sought no professional help or advice for their sexual problems [193], with men more likely to seek treatment for ED than for PE [193]. In the Premature Ejaculation Prevalence and Attitudes (PEPA) survey, only 9% of men with self-reported PE consulted a physician [182]. The main reasons for not discussing PE with their physician are embarrassment and a belief that there is no treatment. Physicians are often uncomfortable discussing sexuality with their patients usually because of embarrassment and a lack of training or expertise in treating PE [705, 706]. Physicians need to encourage their patients to talk about PE. 6.2.4 Classification There is still little consensus about the definition and classification of PE [707]. It is now universally accepted that “premature ejaculation” is a broad term that includes several concepts belonging to the common category of PE. The most recent definition comes from the International Classification of Diseases 11th Revision, where PE was renamed as Early Ejaculation [708]: “Male early ejaculation is characterized by ejaculation that occurs prior to or within a very short duration of the initiation of vaginal penetration or other relevant sexual stimulation, with no or little perceived control over ejaculation. The pattern of early ejaculation has occurred episodically or persistently over a period of at least several months and is associated with clinically significant distress.” This definition includes four categories: male early ejaculation, lifelong generalised and situational, acquired generalised and situational, unspecified. In the Diagnostic and Statistical Manual of Mental Disorders V (DSM-V), PE is defined as a sexual disorder with: • consistent ejaculation within 1 minute or less of vaginal penetration; • over a period of at least 6 months; • experienced 75–100% of the time; • the condition results in clinically significant distress, sexual frustration, dissatisfaction, or tension between partners; • this condition is not better accounted for by another non-sexual mental disorder, medication or illicit substance use, or medical condition [200]. The EAU Guidelines have adopted the definition of PE that was developed by the International Society for Sexual Medicine as the first evidence-based definition [709]. According to this definition, PE (lifelong and acquired) is a male sexual dysfunction characterised by the following: • ejaculation that always or nearly always occurs prior to or within about 1 minute of vaginal penetration (lifelong PE) or a clinically significant and bothersome reduction in latency time, often to about 3 minutes or less (acquired PE); 68

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• •

inability to delay ejaculation on all or nearly all vaginal penetrations; negative personal consequences, such as distress, bother, frustration, and/or the avoidance of sexual intimacy.

Two more PE syndromes have been proposed [668]: • ‘Variable PE’ is characterised by inconsistent and irregular early ejaculations, representing a normal variation in sexual performance. • ‘Subjective PE’ is characterised by subjective perception of consistent or inconsistent rapid ejaculation during intercourse, while ejaculation latency time is in the normal range or can even last longer. It should not be regarded as a symptom or manifestation of true medical pathology. The addition of these new syndrome types may help in overcoming the limitations of each individual definition and it may support a more flexible view of PE for patient stratification, diagnosis and treatment [710]. 6.2.5 Diagnostic evaluation Diagnosis of PE is based on the patient’s medical and sexual history [189, 711, 712]. History should c